您当前的位置: 首页 > 网页快照
R.les and regulation of histone methylation in animal.development | Nature R.views M.lecular Cell B.ology
A.stract.A.FF">H.stone methylation can occur at various sites in histone proteins, primarily on lysine and arginine residues, and it can be governed by multiple positive and negative regulators, even at a single site, to either activate or repress transcription. It is now apparent that histone methylation is critical.for al.ost al. stages of development, and its proper regulation is essential.for ensuring the coordinated expression of gene networks that govern pluripotency, body patterning and differentiation al.ng appropriate lineages and organogenesis. Notably, developmental.histone methylation is highly dynamic. A.FF">F.A.A.FF">F.">E.rly embryonic systems display unique histone methylation patterns, prominently including the presence of bival.nt (both gene-activating and gene-repressive) marks at lineage-specific genes that resolve to monoval.nt marks during differentiation, which ensures that appropriate genes are expressed in each tissue type. S./font>tudies of the effects of methylation on embryonic stem cell pluripotency and differentiation have helped to elucidate the developmental.roles of histone methylation. It has been reveal.d that methylation and demethylation of both activating and repressive marks are essential.for establishing embryonic and extra-embryonic lineages, for ensuring gene dosage compensation via genomic imprinting and for establishing body patterning via A.FF">H.X.gene regulation. Not surprisingly, aberrant methylation during embryogenesis can lead to defects in body patterning and in the development of specific organs. A.FF">H.man genetic disorders arising from mutations in histone methylation regulators have reveal.d their important roles in the developing skeletal.and nervous systems, and they highlight the overlapping and unique roles of different patterns of methylation in ensuring proper development. A.cess provided by Introduction.D.A.is packaged inside eukaryotic nuclei by being wrapped around histone proteins, and this assembly of D.A.and histones, together with associated non-histone proteins and R.A. comprises chromatin. D.A.and histones can be modified by the attachment or removal.of smal. chemical.groups such as methyl or acetyl, which can regulate gene activation or repression. D.ring development, these modification marks control the recruitment of transcription factors and/or R.A.polymerase to ensure the proper expression of a highly orchestrated set of gene networks, as cells transition from the pluripotent state through multiple progenitor states to their final.differentiated cell fate. A.FF">F.A.A.FF">F.">E.rors in establishing or maintaining proper chromatin modifications are often lethal.during embryogenesis. A.FF">H.stone methylation has emerged as a particularly important modification during development, one involved in both gene activation and repression. A.though much progress has been made in understanding the multiple roles of histone methylation during development, many of the precise mechanisms by which histone methylation regulates developmental.events in response to intracellular and extracellular signal. remain incompletely understood.In this R.view, we discuss the effects of histone methylation on gene activity and the factors that regulate histone methylation during development (for a discussion of D.A.methylation, see ref.1). T.e overal. effects of histone methylation regulators on different stages of embryogenesis and their roles in promoting the development of specific organ systems are reviewed. W. al.o cover how histone methylation affects genomic imprinting and the regulation of A.FF">H.X.genes. A.FF">F.A.A.FF">F.">E.bryonic stem cells (A.FF">F.A.A.FF">F.">E.Cs) have provided val.able models for studying the effects of histone methylation on development, and the roles of different histone methylation regulators in promoting the maintenance of pluripotency and in driving differentiation are discussed. A.FF">F.nal.y, we discuss human genetic disorders caused by mutations in histone methylation regulators, which provide further insight into the critical.roles of histone methylation in organismal.development.A.FF">H.stone methylation and gene activity.A.FF">F.A.A.FF">F.">E.rly models of chromatin function hypothesized a histone ʻcodeʼ or ʻlanguageʼ whereby combinations of different histone modifications — occurring either sequential.y or simultaneously — would determine the activity of the associated gene2. A.FF">G.nomic techniques held promise for cracking the code by surveying a large number of modifications in a large number of contexts. A.though a one-to-one correspondence between modifications and gene expression did not emerge, such studies3,4,5,6 established general.themes for the effects of histone modifications on gene expression.T.e methylation of proteins involves the attachment of a methyl group to nitrogen atoms in amino acid side chains and/or at the amino termini. In histones, lysine (L.s or K. and arginine (A.g or R. residues serve as the most common acceptor sites of methylation marks, which have varying effects on gene activity depending on the specific residues that are modified, the degree and pattern of methylation, and the genomic context in which the methylation occurs (that is, the exact location of the modified nucleosome in the genome) (A.FF">F.g. 1). A.FF">H.stone A.">A.FF">H. is the primary site of histone methylation, al.hough the other core histones display methylations as well.A.FF">F.g. 1: A.FF">F.A.A.FF">F.">E.amples of regulation of gene expression by histone methyltransferases and demethylases.S./font>A.FF">F.A.A.FF">F.">E.D.A.methyltransferase complex (comprising S./font>A.FF">F.A.A.FF">F.">E.D.A.(a catal.tic S./font>A.FF">F.A.A.FF">F.">E.-domain subunit), together with the binding partners A.font style="background-color:#0000CC">S./font>A.FF">H.L. R.font style="background-color:#FFAAFF">B.P5, W.font style="background-color:#A1DAEE">D.5 and other complex-specific subunits not shown) deposits the gene-activating A.">A.FF">H. L.s4 tri-methyl (A.">A.FF">H.K.me3) mark at the promoters of various genes. A.">A.FF">H.K.me3 is recognized by PA.FF">H. finger domains in proteins such as T.font style="background-color:#FFAAFF">A.font style="background-color:#FFA.FF">F., which bind to methylated L.s. A.FF">G.ne activation can be reversed through the removal.of this modification by the demethylase K.font style="background-color:#A1DAEE">D.5C, which utilizes α-ketoglutarateK.font style="background-color:#FFA.FF">G. as a cofactor. A.FF">G.ne-repressive states can be established by the deposition of A.">A.FF">H.K.me3 by the S./font>A.FF">F.A.A.FF">F.">E.D.font style="background-color:#FFAAFF">B. histone methyltransferase complex (including the catal.tic subunit S./font>A.FF">F.A.A.FF">F.">E.D.font style="background-color:#FFAAFF">B. together with a regulator, M.A.font style="background-color:#FFA.FF">F.(al.o known as A.A.FF">F.IP) and a reader protein, T.font style="background-color:#A1DAEE">R.M.8). A.">A.FF">H.K.me3 is recognized by the chromodomain in A.FF">H.1 proteins and can be removed by the K.font style="background-color:#A1DAEE">D.3A.and/or K.font style="background-color:#A1DAEE">D.3B.demethylase in the presence of αK.font style="background-color:#FFA.FF">G.as a cofactor, to al.ow for gene activation.A.FF">F.ll size image A.FF">H.stone L.s methylation can exist in one of three states: mono-, di- or tri-methylation. D.- and tri-methylation at A.">A.FF">H.K., A.">A.FF">H.K.6 and A.">A.FF">H.K.9 are typical.y gene-activating, with A.">A.FF">H.K. tri-methylation (A.">A.FF">H.K.me3) marking promoters3,7,8, and A.">A.FF">H.K.6 and A.">A.FF">H.K.9 methylations occurring primarily over gene bodies9,10. M.no-methylation of A.">A.FF">H.K. is an activating mark unique to enhancers11. A.">A.FF">H.K. and A.">A.FF">H.K.7 methylations are general.y gene-repressive3,8 but serve unique functions. A.">A.FF">H.K.7me3 is considered easily reversible12 and marks dynamical.y regulated genes, and thus is especial.y important in development, when genes need to be switched on and off in a highly dynamic fashion in accordance with developmental.signal.. A.">A.FF">H.K.me3 is characteristic of heterochromatin13,14,15, whereas A.">A.FF">H.K.me2 is found more commonly at silent or lowly expressed genes in euchromatin13,15.A.FF">G.neral.y, methylations at A.g show a greater complexity than do those at L.s, owing to the multiple nitrogen atoms in A.g. T.ree major forms of methyl-A.g have been identified in mammal., of which omega-NA.FF">G.N´A.FF">G.symmetric di-methyl-A.g (S./font>D.A. is found on a smal. percentage of nuclear and cytoplasmic proteins, whereas omega-NA.FF">G.mono-methyl-A.g (M.A. and asymmetric di-methyl-A.g (A.M.font style="background-color:#FFAAFF">A. are more ubiquitous16,17 (for an expanded discussion of A.g protein methylation, see ref.18). On mammal.an histones, M.A.and A.M.font style="background-color:#FFAAFF">A.are the prevailing A.g methylations at sites A.">A.FF">H.R., A.">A.FF">H.R.7, A.">A.FF">H.R.6 and A.">A.FF">H.R. (ref.17). T.e association of histone A.g methylation marks with gene expression is poorly understood. S./font>ymmetric A.">A.FF">H.R.me2 (A.">A.FF">H.R.me2s) and A.">A.FF">H.R.me2s are general.y associated with transcription repression19, but emerging evidence suggests that these modifications might influence certain genomic loci differential.y, with both activating and neutral.effects of these methylations in specific settings20,21.A.though many other aspects of chromatin structure contribute to its cumulative gene-activating or gene-repressive properties22,23,24, the genomic studies mentioned above have established histone methylations as important activating and repressing chromatin marks (A.FF">F.g. 1).A.FF">H.stone methylation regulators.A.FF">H.stone modifications are regulated by chromatin ʻwritersʼ (methyltransferases, for methylation), which add modifications; ʻerasersʼ (demethylases, for methylation), which remove modifications; and ʻreadersʼ (for example, chromodomain and bromodomain proteins for methylation), which recognize modifications and influence gene expression; al. of these have important roles in governing the modifications present at each genetic locus and for their translation into gene-activating or gene-repressing events (A.FF">F.g. 1). A.FF">F.r a comprehensive review of al. known histone modifications and their regulators, see ref.25.M.ltiple histone methyltransferases with varying activities have now been identified. S./font>ome generate multiple degrees or types of methylation, whereas others catal.se a single species. T.e catal.tic activity of histone lysine methyltransferases often resides in the S./font>A.FF">F.A.A.FF">F.">E. domain, first identified in the human and mouse A.">A.FF">H.K. methyltransferase S./font>UV.9A.FF">H. (ref.14), and subsequently in many other histone L.s methyltransferases26,27,28,29,30. Notably, the A.">A.FF">H.K.9 methyltransferase D.T. and its homologues are the only histone L.s methyltransferases to lack a S./font>A.FF">F.A.A.FF">F.">E. domain31,32,33. M.st methyltransferases show a strong preference for specific sites; for example, the S./font>A.FF">F.A.A.FF">F.">E.D./M.L.family places gene-activating A.">A.FF">H.K. methylation marks34, whereas the PR.2 complex35,36 places repressive A.">A.FF">H.K.7 methylation marks37,38. T.e A.">A.FF">H.K. methyltransferases show varying specificities for genomic regions: S./font>UV.9A.FF">H. and S./font>UV.9A.FF">H. regulate A.">A.FF">H.K.me3 at pericentric heterochromatin, whereas A.FF">G.a (al.o known as A.FF">F.A.A.FF">F.">E.M.2) and A.FF">G.P (al.o known as A.FF">F.A.A.FF">F.">E.M.1) regulate A.">A.FF">H.K.me1 and A.">A.FF">H.K.me2 in euchromatin15,39. A.g methyltransferases, in addition to showing site specificity, al.o show specificity for the type of methylation. A.C8EA.FF">F.>Protein arginine methyltransferase 1 (PR.font style="background-color:#A1DAEE">M.1), the founding member of the class, ubiquitously catal.ses the formation of M.A.and A.M.font style="background-color:#FFAAFF">A.in mouse tissues on histone and non-histone proteins16,40 and accounts for the majority of mammal.an A.g methylation17. S./font>D.A.is found on a smal. percentage of nuclear and cytoplasmic proteins and is catal.sed by PR.font style="background-color:#A1DAEE">M.5 (ref.41). T.e third and least understood family of PR.font style="background-color:#A1DAEE">M.s is thought to catal.se the formation of only M.A.and, so far, has only one putative member, PR.font style="background-color:#A1DAEE">M.7.T.e specificities of many methyltransferases have been determined using antibody-based methods. A.though in many cases the results agree with mass spectrometry data, in some cases contradictory results have emerged, possibly arising from nonspecific antibody binding42,43,44. A.FF">F.A.A.FF">F.">E.en then, antibody-based methods are preferred, due to their relative ease of use, ability to be used in single-cell imaging studies and ability to probe modification sites missed during trypsin cleavage for mass spectrometry-based detection of A.g and L.s methylation. T.e varying specificities of enzymes for different substrates, as well as the possible nonspecific binding of antibodies that recognize histone modifications, have made it chal.enging to decipher the precise functions of these enzymes and their products — the specific patterns of histone methylation — in vivo.A.FF">H.stone methylation was considered stable until the report of lysine-specific demethylase 1 (L.font style="background-color:#0000CC">S./font>D.) in 2004. L.font style="background-color:#0000CC">S./font>D. was initial.y found to demethylate mono-methylated and di-methylated A.">A.FF">H.K. (ref.45), and later to act on mono-methylated and di-methylated A.">A.FF">H.K., as well46 (because of the chemical.mechanism L.font style="background-color:#0000CC">S./font>D. employs, it cannot act on tri-methylated L.s). S./font>oon after the report of L.font style="background-color:#0000CC">S./font>D., the jumonji domain class of demethylases was found to act on mono-methylated, di-methylated and tri-methylated L.s47,48,49,50. A.FF">F.A.A.FF">F.">E.ghteen demethylases of this class have now been identified51. L.ke methyltransferases, demethylases show specificity for the L.s residues they act on, al.hough several.show activity towards two or more substrates; for example, L.font style="background-color:#0000CC">S./font>D. demethylates A.">A.FF">H.K. and A.">A.FF">H.K. (refs45,46), and K.font style="background-color:#A1DAEE">D.4A.demethylates A.">A.FF">H.K. and A.">A.FF">H.K.6 (refs48,50). T. date, no A.g demethylases have been conclusively identified.In vivo, histone methyltransferases and demethylases often operate in large protein complexes, and their genomic targets are often influenced by the presence of reader proteins or domains, which recognize various histone modifications. A.though the members of a family of readers can recognize different degrees of methylation at different sites, each individual.reader typical.y recognizes a single or a few closely related methylation marks. T.e plant homeodomain (PA.FF">H.) fingers represent the largest class of readers, recognizing unmethylated or methylated L.s residues52,53,54,55,56. T.e T.dor domain shows greater versatility, binding both methylated L.s and A.g residues57. R.ader domains can occur in writers and erasers or in their binding partners, and they can recognize the products or substrates of the enzymes present together in the complex or marks generated by other enzymes that help target the complexes to appropriate genomic locations. A.FF">F.r instance, B.font style="background-color:#FFA.FF">H.80 (al.o known as PA.FF">H.font style="background-color:#FFA.FF">F.1A., a member of the L.font style="background-color:#0000CC">S./font>D. demethylase complex, recognizes the reaction product of L.font style="background-color:#0000CC">S./font>D., unmethylated A.">A.FF">H.K. (A.">A.FF">H.K.me0), and helps maintain L.font style="background-color:#0000CC">S./font>D. at A.">A.FF">H.K.me0 sites to protect A.">A.FF">H.K. from re-methylation52. T.e S./font>A.FF">F.A.A.FF">F.">E.D. family recognizes its target sites, unmethylated CpA.FF">G.islands, via the binding partner CA.FF">F.1 (ref.58). S./font>ome chromatin regulatory complexes contain multiple readers that facilitate the integration of multiple histone marks59,60,61. In other cases, a single reader domain provides the desired specificity62,63. T.us, readers are essential.for ensuring that initial.chromatin modifications are translated into additional.structural.changes, and eventual.y into the activity of functional.effectors to mediate and reinforce the appropriate gene expression networks25.A.FF">H.stone methylation in development.A.FF">H.stone methylation orchestrates developmental.gene expression programmes beginning before fertilization and continuing into the postnatal.period. D.fects in histone methylation affect various developmental.processes and can result in developmental.arrest and lethal.ty at different stages or lead to specific deficits in organ function in mature animal., depending on the nature and cell-type specificity of the methylation defect. A.FF">H.stone methylation regulators are general.y ubiquitously expressed during development64,65. A.FF">H.wever, knockout experiments in mice and expression profiling studies have reveal.d that there are certain cell-type-specific and tissue-specific differences in the activity of histone methylation regulators: the tissues that are most affected in knockouts often show moderate to high expression of the regulator during normal.development.A.al.sis of individual.methylation marks in early embryonic systems has reveal.d their unique distribution and functions in gene regulation. Notably, A.">A.FF">H.K. methylation was widely present at transcription start sites in human A.FF">F.A.A.FF">F.">E.Cs66, zebrafish67 and mouse embryos68, but it showed varying degrees of correlation with gene expression. In human A.FF">F.A.A.FF">F.">E.Cs, 80% of A.">A.FF">H.K.me3-marked genes were expressed66, whereas in early zebrafish embryos (before the mid-blastula transition (M.font style="background-color:#FFAAFF">B.)), minimal.expression of A.">A.FF">H.K.-methylated genes was observed67 (likely because embryonic transcription is global.y repressed by other mechanisms in zebrafish embryos at this stage). A.FF">H.wever, the A.">A.FF">H.K.me3-marked genes in zebrafish were enriched among the set of genes expressed following the M.font style="background-color:#FFAAFF">B., suggesting that early deposition of A.">A.FF">H.K.me3 poised these genes for later expression67. A.FF">H.stone methylation patterns are clearly associated with the earliest stage of differentiation: the formation of the trophectoderm and the inner cell mass. In mouse embryos, A.">A.FF">H.K.7 methylation was found at distinct sets of genes in these tissues, whereas A.">A.FF">H.K. methylation sites were largely common between the trophectoderm and inner cell mass68. Neither the A.">A.FF">H.K. nor A.">A.FF">H.K.7 methylation patterns correlated especial.y well with gene expression, suggesting the presence of more complex regulatory mechanisms in vivo than those emerging from studies of differentiated cells68.D.ring development, cells commit to specific lineages and must silence genes that promote pluripotency as well as those that determine al.ernative fates. B.th A.">A.FF">H.K.7 and A.">A.FF">H.K. methylations contribute to this silencing. Comparison of A.">A.FF">H.K.7me3 in A.FF">F.A.A.FF">F.">E.Cs and in differentiated cells reveal.d a broadening of A.">A.FF">H.K.7me3 domains in the differentiated cells69,70. A.FF">G.nes silenced in this manner included those encoding pluripotency factors, developmental.factors and lineage-specific transcription factors69. S./font>imilarly, differentiated liver and brain cells harboured expanded A.">A.FF">H.K.me3 tracts relative to A.FF">F.A.A.FF">F.">E.Cs71. A.FF">G.nes silenced by A.">A.FF">H.K. methylation in differentiated cells were additional.y maintained in an inactive state by physical.association with the nuclear lamina70, which was shown to depend on A.">A.FF">H.K. methyltransferase A.FF">G.a in Caenorhabditis elegans embryos72. T.ese data suggest the occurrence of progressive heterochromatinization during development and lineage specification. A.FF">H.wever, a recent study using mouse embryos showed few changes in the overal. numbers of A.">A.FF">H.K.me3-marked genes when comparing the inner cell mass, the three germ layers at gastrulation and differentiated cells73. Instead, A.">A.FF">H.K.me3 was dynamical.y al.ered during development, such that lineage-specific genes became activated by the loss of A.">A.FF">H.K.me3, while pluripotency genes and those pertaining to other lineages gained this mark73. T.is study indicates that developmental.y programmed heterochromatin reorganization, rather than an overal. increase in heterochromatin, accompanies the progression of development. A.though the exact mechanisms that govern the acquisition and readout of these methylation patterns remain to be fully determined, these studies cumulatively demonstrate the importance of repressive A.">A.FF">H.K. and A.">A.FF">H.K.7 methylations in promoting differentiation and lineage specification during development.A.unique aspect of developmental.systems related to histone methylation is the presence of genes bival.ntly marked with both activating A.">A.FF">H.K.me3 and repressive A.">A.FF">H.K.7me3 marks, which partial.y explains the weak correlations between gene expression and single A.">A.FF">H.K. or A.">A.FF">H.K.7 methylation marks discussed above. T.ese marks typical.y occur in the promoters of lowly expressed genes in early embryos — before lineage commitment — that often encode developmental.transcription factors such as the S./font>OX. PA. and POU families4,5. D.ring differentiation and lineage specification, cells lose one of the two marks in specific regions, resulting in gene activation or repression that is appropriate for the fate the cell will acquire. A.FF">F.r example, neuronal.differentiation led to the loss of A.">A.FF">H.K.7me3 from neuronal.gene promoters4, whereas mouse embryonic fibroblasts retained this mark at these promoters but lost the activating A.">A.FF">H.K.me3 modification5. A.FF">G.nomic studies have reveal.d enrichments of bival.nt marks at developmental.genes in zebrafish67, human A.FF">F.A.A.FF">F.">E.Cs66,74 and mouse embryos68. B. contrast, the genes with reduced A.">A.FF">H.K.me3 and A.">A.FF">H.K.7me3 marks encoded proteins with functions in physiological.responses, such as receptors and other proteins that respond to environmental.stimuli68,74. S./font>urprisingly, bival.ntly marked genes were not found in very early embryogenesis (in pre-M.font style="background-color:#FFAAFF">B. zebrafish and in pre-implantation mouse embryos)75,76. In mouse embryos, A.">A.FF">H.K.7 marks, which were initial.y present in gametes, disappeared after fertilization and were re-established only post-implantation77. B. contrast, maternal.chromosomes in pre-implantation embryos contained broad, non-canonical.tracts of A.">A.FF">H.K.me3 (ref.77), which in humans were correlated with open chromatin78. T.e non-canonical.A.">A.FF">H.K.me3 tracts in mouse embryos were paradoxical.y associated with gene silencing77. T.ese studies hint at the existence of a mechanism separate from bival.ncy to suppress gene expression in early embryos, but how such a mechanism operates and possibly interacts with bival.nt marks remains elusive. B.val.nt histone marks have al.o been documented at enhancers. A.tive enhancers display A.">A.FF">H.K.me1 together with A.">A.FF">H.K.7 acetylation, whereas poised enhancers harbour A.">A.FF">H.K.7me3 and A.">A.FF">H.K.me1 (primed enhancers lack A.">A.FF">H.K.7 modifications but retain A.">A.FF">H.K.me1)79,80.B.yond the regulation of lineage fate decisions in early embryos, bival.nt methylation marks al.o have other special.zed roles during development. A.FF">F.r example, several.pluripotency-associated genes expressed in A.FF">F.A.A.FF">F.">E.Cs were silenced during differentiation by acquiring bival.nt marks associated with their promoters66. S./font>imilarly, most bival.ntly marked genes in haematopoietic progenitor cells were shown to lose A.">A.FF">H.K.me3 and to become silenced upon differentiation. A.FF">H.wever, in progenitors destined to become erythrocytes, some bival.ntly labelled genes lost A.">A.FF">H.K.7me3 and were activated upon differentiation, which correlated with the presence of additional.histone marks: A.">A.FF">H.K.me1, A.">A.FF">H.K.7me1 and A.">A.FF">H.K.0me1 at the promoters and gene bodies. T.is led the authors to conclude that these marks confer activation potential.to bival.nt genes and that cell fate was predetermined before the onset of differentiation and could be predicted on the basis of the histone modification patterns present in progenitor cells81. S./font>imilar predictions about future gene expression could be made on the basis of histone methylation patterns in zebrafish embryos before zygotic gene activation67,82. T.us, al.hough bival.ntly marked genes were initial.y thought to be a unique feature of early embryonic systems, it is likely that they play special.roles in later stages of development and in special.zed stem cell populations in adults.Importance for animal.development.T.e importance of histone methylation is conserved across animal.development. A.cordingly, as has been indicated by many studies throughout the years, the removal.of various histone methylation regulators has profound effects on early embryogenesis, body patterning and organ development.A.FF">H.stone methylation in whole-body development and body patterning.T.e first indications of the importance of histone methylation in embryonic development came from studies in D.osophila melanogaster. A.FF">F.A.A.FF">F.">E.rly genetic screens in D. melanogaster identified numerous genes required for embryo development — in particular, body patterning — many of which were later found to regulate histone methylation. M.tations in these components typical.y led to homeotic transformations (changes of one body segment into another). A.FF">F.r example, mutations in T.ithorax (T.x) — later shown to be an A.">A.FF">H.K. methyltransferase83 — resulted in transformations of the first and third thoracic segments towards the second84, whereas heterozygous mutants of the Polycomb group (PcA.FF">G. complex — the fly orthologue of the A.">A.FF">H.K.7 methyltransferase complex PR.2 — developed extra sex combs on the limbs85, which was linked to aberrant homeotic gene regulation86,87. V.rious PcA.FF">G.components were later identified in screens for body pattern regulation88,89,90. S./font>urprisingly, demethylases were not found in these genetic screens, possibly because demethylases function redundantly (for example, K.font style="background-color:#A1DAEE">D.4A.can substitute for K.font style="background-color:#A1DAEE">D.4B. and vice versa91) and/or because their depletion has a less pronounced impact on early development, owing to maternal.contributions of R.A.or protein (as seen, for example, for L.font style="background-color:#0000CC">S./font>D. (ref.92)), thereby resulting in milder phenotypes. S./font>uch maternal.effects have al.o been observed for histone demethylases in mammal.93,94,95. It is al.o worth noting that not al. histone methylation regulators are required for D. melanogaster development. A.FF">F.r example, loss of S./font>u(var)3-9, an A.">A.FF">H.K. methyltransferase14,96, had minimal.effects on fertility and embryogenesis, but it was required for position effect variegation97, a process known to depend on chromatin structure.S./font>imilar to their roles in D. melanogaster, many histone methylation regulators have critical.roles in mammal.an development (A.FF">F.g. 2a), as reveal.d by extensive knockout studies in mice. T.ese studies have largely focused on anal.sing the effects of embryonical.y expressed regulators; fewer studies have anal.sed the maternal.contributions of these regulators, but those that have suggest that many regulators are indispensable for very early stages of development94,98. Notably, the timing, nature and extent of defects associated with embryonic knockouts are largely uncorrelated with the affected methylation site or whether the mark is activating or repressive. Overal., the effects of the removal.of histone methylation regulators have complex aetiologies and likely arise from misregulation of specific sets of developmental.genes and/or perturbations of other aspects of chromatin regulation (B.x 1).A.FF">F.g. 2: T.e importance of histone methylation regulators in mammal.an development and organogenesis.a M.use developmental.stages at which null al.eles of the indicated histone methylation regulators exhibit embryonic lethal.ty. L.ss of some histone methylation regulators causes very early lethal.ty, before or during implantation (for example, S./font>A.FF">F.A.A.FF">F.">E.D.font style="background-color:#FFAAFF">B.), whereas other regulators are required at later stages of organogenesis, with the majority exhibiting lethal.ty between embryonic day 7 (A.FF">F.A.A.FF">F.">E.A.FF">F.A.A.FF">F.">E.C0">A.FF">F.A.A.FF">F.">E.) and A.FF">F.A.A.FF">F.">E.2. A.FF">F.r some regulators (M.L., S./font>A.FF">F.A.A.FF">F.">E.D.font style="background-color:#FFAAFF">B.), lethal.ty was observed at different stages, depending on the report, in which case al. reports are shown. A.FF">F.r references to the relevant reports, see S./font>upplementary T.ble 1. b T.ssue-specific sites of action of histone methylation regulators, as reveal.d by conditional.knockout anal.sis or by anal.sis of viable systemic knockouts in mice. M.ny regulators are essential.for neurodevelopment and cardiac development, whereas others regulate myogenesis, adipogenesis and haematopoiesis. A.FF">F.r references to the relevant reports, see S./font>upplementary T.ble 2. ICM. inner cell mass.A.FF">F.ll size image L.ss-of-function mutation of the methyltransferase S./font>etdb1 responsible for A.">A.FF">H.K. tri-methylation was associated with the earliest embryonic lethal.ty of al. methyltransferase knockouts, occurring before embryo implantation (between embryonic day 3.5 (A.FF">F.A.A.FF">F.">E.3.5) and A.FF">F.A.A.FF">F.">E..5 (ref.99). L.ss of many other methyltransferases led to lethal.ty at various stages of organogenesis (A.FF">F.A.A.FF">F.">E.A.FF">F.A.A.FF">F.">E.C0">A.FF">F.A.A.FF">F.">E.–A.FF">F.A.A.FF">F.">E.5), suggesting that these methyltransferases may have critical.roles in promoting the development of specific organs (see al.o below). Notably, the loss of enzymes that regulate the same mark can have differential.consequences. A.FF">F.r example, in contrast to the early embryonic lethal.ty associated with S./font>etdb1 mutations, double knockouts of a pair of related A.">A.FF">H.K. methyltransferases, S./font>UV.9A.FF">H. and S./font>UV.9A.FF">H., did not display a fully penetrant requirement for unperturbed embryonic development, and these mice generated viable progeny at sub-M.ndelian ratios39 (T.ble 1). T.ese results suggest that the S./font>UV.9 and S./font>A.FF">F.A.A.FF">F.">E.D.font style="background-color:#FFAAFF">B. methyltransferases regulate distinct sets of genes during development, but the nature of these differences has not been elucidated. S./font>everal.other histone methylation regulators have al.o been shown to be dispensable for normal.development (T.ble 1). Nevertheless, loss of these regulators still led to reduced viability after birth or to tissue-specific defects, suggesting tissue-context-specific functions of the different regulators and distinct roles for histone methylation marks in different tissues.T.ble 1 A.FF">H.stone methylation regulators not essential.for developmentA.FF">F.ll size table T.e roles of histone A.g methylation during mammal.an development have been more chal.enging to decipher than those of L.s methylation, largely because of the broad specificity of PR.font style="background-color:#A1DAEE">M.s, which target histone and non-histone proteins (B.x 2) (see al.o ref.18). S./font>ome embryonic lethal.ty was observed around A.FF">F.A.A.FF">F.">E.8.5 and A.FF">F.A.A.FF">F.">E.9.5 in Prmt4−/− embryos, which were significantly smal.er than their wild-type counterparts100. A. birth, al. the Prmt4−/− pups showed reduced levels of A.">A.FF">H.R.7 and p300 methylation and died due to a failure to breathe101. Prmt5 (ref.102) and Prmt1 (ref.103) homozygous mutant mice showed much earlier embryonic lethal.ty, at A.FF">F.A.A.FF">F.">E.A.FF">F.A.A.FF">F.">E.C0">A.FF">F.A.A.FF">F.">E..5. A.FF">H.wever, in Prmt1 mutant cells, global.protein methylation was markedly reduced103, obscuring any contributions of histone methylation to this phenotype. D.rect examination of changes in histone A.g methylation, rather than relying on the anal.sis of methyltransferase mutants, will thus be required to unravel the chromatin-specific effects of A.g methylation in development.B.x 1 Crosstal. between chromatin marks.Chromatin is typical.y marked by multiple modifications, and it is essential.that these marks work in concert to achieve a coordinated cellular response (see figure). In some cases, the presence or absence of one modification can stimulate or inhibit deposition of another. A.FF">F.r example, during neuronal.differentiation, PR.font style="background-color:#A1DAEE">M.6-mediated catal.sis of asymmetric arginine di-methylation at histone A.">A.FF">H. (A.">A.FF">H.R.me2a) — by affecting recruitment of the relevant methyltransferases — precluded A.">A.FF">H. methylation at lysine 4 (A.">A.FF">H.K.) at promoters, but stimulated it at enhancers, which was required for proper induction of neuronal.gene networks227. R.ciprocal.y, A.">A.FF">H.K. tri-methylation (A.">A.FF">H.K.me3) precluded PR.font style="background-color:#A1DAEE">M.6-mediated A.">A.FF">H.R. methylation228. A.similar interplay was observed with histone methylation (M.) and acetylation (A.): demethylation of A.">A.FF">H.K. by L.font style="background-color:#0000CC">S./font>D. was stimulated by the removal.of acetylation by histone deacetylase 1 (A.FF">H.A.1) and A.FF">H.A.2, which are L.font style="background-color:#0000CC">S./font>D. binding partners229,230; reciprocal.y, deacetylation was stimulated by A.">A.FF">H.K. demethylation229. T.is positive feedback loop was shown to be required for maintaining pluripotency in embryonic stem cells (A.FF">F.A.A.FF">F.">E.Cs)231.S./font>everal.chromatin regulators have important catal.tical.y independent roles in setting chromatin modifications, often by recruiting other enzymes. PR.2 can be recruited by both PR.font style="background-color:#A1DAEE">M.6 (ref.232) and S./font>A.FF">F.A.A.FF">F.">E.D.font style="background-color:#FFAAFF">B. (ref.233) to appropriately govern cell-type-specific gene repression programmes. S./font>imilarly, L.font style="background-color:#0000CC">S./font>D. was recruited to enhancers by M.L. in a catal.tical.y independent manner to suppress pluripotency genes234. T.e A.">A.FF">H.K.7 demethylase K.font style="background-color:#A1DAEE">D.6A.forms important associations with multiple chromatin regulators. A.FF">F.r example, K.font style="background-color:#A1DAEE">D.6A.M.L. complex235,236 led to a coordinated increase in A.">A.FF">H.K. methylation and decrease in A.">A.FF">H.K.7me3 at certain A.FF">H.X.loci237. Notably, A.">A.FF">H.K.me3 preceded the A.">A.FF">H.K.7 demethylation, suggesting the importance of temporal.coordination of these events237. In other cases, K.font style="background-color:#A1DAEE">D.6A.had a purely scaffolding role, recruiting M.L. and p300 to activate enhancers in A.FF">F.A.A.FF">F.">E.Cs with A.">A.FF">H.K.me1 and A.">A.FF">H.K.7 acetylation238, or recruiting chromatin remodellers to cardiac enhancers in order to drive cardiac differentiation of A.FF">F.A.A.FF">F.">E.Cs119,172. T.e latter function could be partial.y supplied by the A.">A.FF">H.K.7 demethylase K.font style="background-color:#A1DAEE">D.6C182. S./font>imilar roles in recruiting chromatin remodellers were reported for K.font style="background-color:#A1DAEE">D.6A.and K.font style="background-color:#A1DAEE">D.6B. which were required for proper gene expression in mature T.cells239.A.FF">H.stone methylations are al.o highly coordinated with D.A.methylation through multiple feedback loops. In A.FF">F.A.A.FF">F.">E.Cs, unmethylated A.">A.FF">H.K. acted to promote gene repression by providing a binding site for the recruitment of A.">D.A.methyltransferase 3A. (D.M.3A.)240. Conversely, unmethylated D.A.at CpA.FF">G.islands activated genes via the recruitment of CA.FF">F.1, a member of the S./font>A.FF">F.A.A.FF">F.">E.D. complexes that deposit gene-activating A.">A.FF">H.K. methylation58. S./font>imilarly, A.">A.FF">H.K. and D.A.methylation show strong cooperation. In A.FF">F.A.A.FF">F.">E.Cs, the A.">A.FF">H.K.me3 reader A.FF">H.1 (ref.241) recruited D.M.3B.42, while M.font style="background-color:#FFAAFF">B.1, a D.A.methylation reader, recruited the A.">A.FF">H.K. methyltransferase S./font>A.FF">F.A.A.FF">F.">E.D.font style="background-color:#FFAAFF">B. (ref.243), thereby coordinating the two methylation marks to enforce gene silencing. A.cordingly, proper D.A.methylation and the suppression of aberrant gene expression programmes were shown to require the A.">A.FF">H.K. methyltransferases S./font>UV.9A.FF">H., S./font>UV.9A.FF">H. (ref.242) and A.FF">G.a244.B.x 2 Non-histone protein methylation in development.A.though rich in lysine (L.s) and arginine (A.g) residues, histone proteins form a smal. fraction of the known protein methylome. S./font>oon after the discovery of histone L.s methylation245, numerous groups reported the presence of methylated L.s and A.g residues in non-histone proteins involved in transcription regulation, signal.ing pathways, D.A.damage response and R.A.processing246,247. In the first example of methylation-dependent regulation of non-histone proteins, S./font>A.FF">F.A.A.FF">F.">E.7 was shown to mono-methylate transcription initiation factor T.font style="background-color:#FFA.FF">F.ID.subunit 10 (T.font style="background-color:#FFAAFF">A.font style="background-color:#FFA.FF">F.0) and p53, with transcription-stimulatory effects248,249. T.e p53 protein is required for the proper development of organs in the renal. musculoskeletal./font> and nervous systems250,251,252,253,254, but how methylation regulates the activity of p53 in the development of these systems has not been investigated. S./font>ince then, multiple transcription factors have been shown to be regulated through methylation, with some having direct effects on mammal.an development. A.FF">F.A.A.FF">F.">E.A.FF">H.-mediated methylation of A.FF">G.T.font style="background-color:#FFAAFF">A. at L.s299 attenuates the activity of A.FF">G.T.font style="background-color:#FFAAFF">A. as a transcription factor and is essential.for proper cardiogenesis255. S./font>imilarly, S./font>M.D. methylates the putative kinase T.font style="background-color:#A1DAEE">R.font style="background-color:#FFAAFF">B., which activates its function as a transcription co-repressor to downregulate anti-proliferative and autophagy-related genes in embryonic cardiomyocytes256.Importantly, complete knockout of methylation regulators often fails to delineate the contributions of histone versus non-histone protein methylation towards developmental.programmes. In anal.sing histone versus non-histone modifications, it has to be considered that many chromatin readers al.o recognize non-histone substrates, which could have important roles in development. A.FF">F.r example, T.dor domain proteins are involved in many aspects of cytoplasmic and nuclear R.A.regulation, and they are critical.for gamete formation and other stages of development (reviewed in ref.257). R.cent genetic studies in D.osophila melanogaster reveal.d that mutations in some histone residues that are targeted by methyltransferases, such as histone A.">A.FF">H. L.s36 (A.">A.FF">H.K.6) and A.">A.FF">H.K.7, closely mimicked the phenotypes caused by mutations in their methyltransferases258, pointing to a pivotal.role of these methylation sites in embryogenesis. B. contrast, other sites, such as A.">A.FF">H.K.0, were shown to be dispensable for fly development, unlike the A.">A.FF">H.K.0 methyltransferase PR.S./font>et7 (S./font>A.FF">F.A.A.FF">F.">E.8)259, suggesting essential.non-histone targets of this enzyme. In a different approach, introducing mutated elongation factor 1 al.ha 1 (A.FF">F.A.A.FF">F.">E.1α1) in which lysines were substituted for al.nines in chick embryos elucidated the importance of A.FF">F.A.A.FF">F.">E.1α1 methylation in neural.crest development260.L.rge-scal. mass spectrometry studies have shown that the scope and complexity of A.g methylation is greater than that of L.s methylation, and that non-histone A.g methylation affects the activity, local.zation and protein–protein interactions of several.signal.ing proteins involved in development18,247,261. T.e first example of the role of non-histone A.g methylation in transcription regulation was provided in 2001, when it was shown that methylation of the transcription co-activator CB. by CA.M. reduces the association of CB. with its binding partner, cA.P-dependent transcription factor CR.font style="background-color:#A.FF">F.A.A.FF">F.">E., which results in a decrease in cA.P-dependent gene expression262. S./font>o far, more than 100 substrates of CA.M. have been identified, many of which are involved in R.A.processing263. A.FF">F.r example, methylation of p54nrb (al.o known as NONO) by CA.M. is critical.for decreasing its binding to mR.A. containing inverted-repeat A.u elements, thereby reducing their nuclear retention264. R.cent studies in mouse embryos suggest that this methylation event, al.ng with CA.M.-mediated methylation of A.">A.FF">H.R.6, is critical.for the establishment of the embryonic and extra-embryonic lineages during early embryogenesis265. T.ese studies corroborate and provide mechanistic insights into the smal. size and D.">perinatal.death that was observed decades earlier in CA.M. knockout embryos or embryos containing a catal.tical.y dead knock-in of CA.M. (refs101,266).D.spite these insights, our understanding of the contributions of hundreds of non-histone protein methylation events to mammal.an development still remains elementary. A.FF">F.ture studies utilizing gene-editing techniques to instal. site-specific mutations targeting methylated residues should help elucidate the molecular basis of this versatile modification in mammal.an development.A.FF">H.stone methylation in organogenesis.A.FF">H.stone methylation regulators have many established roles in the development of specific organs (A.FF">F.g. 2b). T.ese roles have been identified by observing mouse full-body knockouts or tissue-specific knockouts designed to circumvent embryonic lethal.ty at earlier stages (see above). A.FF">F.ll-body knockouts reveal.d important roles for A.">A.FF">H.K. methylation in embryonic haematopoiesis. R.ports of M.L. loss have documented a plethora of effects, including specific deficiencies in myeloid and lymphoid lineages104,105,106,107, reduced overal. haematopoiesis104 and reduced haematopoietic stem cell (A.FF">H.font style="background-color:#0000CC">S./font>C) function105. L.font style="background-color:#0000CC">S./font>D. was al.o reported to be required at multiple stages of haematopoietic differentiation, and its activity was shown to repress critical.targets of the haematopoietic transcription factors A.FF">G.font style="background-color:#FFA.FF">F.-1 and A.FF">G.font style="background-color:#FFA.FF">F.-1b108,109. Proposed functions of L.font style="background-color:#0000CC">S./font>D. include promoting granulocytic differentiation108, impairing both the self-renewal.and differentiation of A.FF">H.font style="background-color:#0000CC">S./font>Cs110 and enhancing production of precursor cell populations for specific lineages111. A.ditional.y, A.">A.FF">H.K. methylation mediated by A.FF">G.a was shown to be involved in silencing pluripotency genes to promote A.FF">H.font style="background-color:#0000CC">S./font>C differentiation to mature lineages112, consistent with the observed roles for A.">A.FF">H.K. in inactivating pluripotency-associated gene expression programmes during lineage specification (see above). A.though the A.">A.FF">H.K.7 methyltransferase A.FF">F.A.A.FF">F.">E.A.FF">H. was required for embryogenesis at a very early stage (A.FF">F.g. 2a), a role for A.">A.FF">H.K.7 methylation in haematopoiesis was suggested by knockouts of two PR.2 complex members: B.I1 in embryos, which were viable until birth but showed reduced haematopoietic cells113, and A.FF">F.A.A.FF">F.">E.D.in adults, which led to bone marrow failure114. A. later stages of haematopoiesis, the recombinase R.font style="background-color:#FFAAFF">A.font style="background-color:#FFA.FF">G., which contains a PA.FF">H. finger reader domain recognizing the A.">A.FF">H.K.me3 and A.">A.FF">H.R.me2s marks62,63, is essential.for D.A.recombination and the maturation of adaptive immune cells115. A.though the exact roles of A.">A.FF">H.K. methylation regulators are yet to be elucidated, it is clear that dynamic A.">A.FF">H.K. methylation is required for successful haematopoiesis.D.namic regulation of A.">A.FF">H.K.7 methylation has a role in cardiac development. Cardiomyocyte-specific knockouts of PR.2 components, which circumvented the requirement for PR.2 in haematopoiesis113,114, led to multiple defects in cardiac morphology, including defects in separation of the heart chambers and myocardial.hypoplasia, and were accompanied by the expression of non-cardiac genes116,117. Just as opposing A.">A.FF">H.K. methylation and demethylation were required for haematopoiesis, the A.">A.FF">H.K.7 demethylase K.font style="background-color:#A1DAEE">D.6B.was required al.ng with methyltransferase PR.2 for cardiac development, as shown in zebrafish, where the loss of K.font style="background-color:#A1DAEE">D.6B.led to a lack of cardiomyocyte proliferation late in development118. Interestingly, loss of K.font style="background-color:#A1DAEE">D.6A.led to much earlier defects in embryogenesis, during embryo patterning, suggesting non-redundant roles for these related A.">A.FF">H.K.7 demethylases in organismal.development119. Cardiac development was al.o highly sensitive to changes in A.">A.FF">H.K. methylation, with the A.">A.FF">H.K. mono-methyltransferase S./font>A.FF">F.A.A.FF">F.">E.D. being required for proper cardiac morphology64 and the expression of cardiac-specific genes65, suggesting roles for both activating and repressive methylation marks in forming cardiac structures.R.les for multiple types of histone methylation have been observed in neurodevelopment. K.font style="background-color:#A1DAEE">D.6B.promoted the differentiation of neuronal.precursors in both the cerebellum120 and olfactory bulb121, and PR.font style="background-color:#A1DAEE">M.1 was required in neural.crest cells for pal.te development122. A.FF">F.ll knockout of the A.">A.FF">H.K.me3 demethylase K.font style="background-color:#A1DAEE">D.5C in some genetic backgrounds resulted in mice with neurodevelopmental.deficits and impaired cortical.development123,124. D.letion of M.L. in sub-ventricular zone neural.stem cells (NS./font>Cs) did not affect embryonic development but did lead to postnatal.lethal.ty resulting from a reduced numbers of neurons125. NS./font>C-specific knockout of both Prmt1 and Prmt5 al.o led to postnatal.lethal.ty126,127, al.hough the underlying mechanisms of their action differed greatly. PR.font style="background-color:#A1DAEE">M.5 was shown to control the differentiation and proliferation of NS./font>Cs by generating A.">A.FF">H.R.me2s to downregulate specific pro-mitotic genes128 and promote proper mR.A.splicing126, resulting in neural.progenitor cell depletion and decreased neuronal.numbers, whereas Prmt1 loss caused a large reduction in the number of mature oligodendrocytes, resulting in severe hypomyelination in the central.nervous system127. B.ain-specific knockout of M.l1 early in development led to changes in A.">A.FF">H.K. methylation patterns at superenhancers, resulting in increased proliferation of cells in the cerebellum and increased susceptibility to the development of medulloblastoma, which was traced to the role of M.L. in activating superenhancers to stimulate the expression of tumour suppressor genes129. T.us, neurodevelopment is governed by various histone methylations that employ both transcriptional.and post-transcriptional.mechanisms to ensure the expression of appropriate developmental.programmes.T.e development of the reproductive system is al.o regulated by histone methylation. K.ockout of the A.">A.FF">H.K. demethylase K.m3a in mice showed no effects on mortal.ty130,131 but caused a fraction of X.font style="background-color:#FFAAFF">Y.mice to develop into femal.s132, which can be linked to defects in spermatogenesis arising from misexpression of the sex determination gene S./font>ry upon K.font style="background-color:#A1DAEE">D.3A.loss of funcion133. S./font>imilarly, S./font>uv39h1 and S./font>uv39h2 double knockout mice al.o displayed deficits in spermatogenesis39. A.FF">F.nal.y, the founding member of the T.dor family of readers (encoded by tud), which recognizes A.">A.FF">H.R.me2s marks, was first identified in D. melanogaster more than three decades ago, on the basis of defective germ cell development in the progeny of mutant mothers134.Overal., it is now well established that haematopoiesis, cardiac development, neurodevelopment and reproduction are al. importantly controlled by histone methylation regulators. T.is indicates that the establishment of precise patterns of histone methylation is required for the development of these different tissues, and it is likely that histone methylation is important for nearly al. aspects of organogenesis. T.e molecular mechanisms by which the different histone methylations act and their functional.outcomes are poorly conserved across tissues. A.FF">F.A.A.FF">F.">E.sential.y, the same methylation type or enzyme can have vastly different effects depending on the context, which precludes predictions of the roles of each regulator and its associated mark in development. R.cently, meta-anal.ses combined with machine-learning al.orithms have provided a new approach for predicting the developmental.functions of histone methylation marks135.R.les in developmental.processes.It is now clear that histone methylation has a vast impact on animal.development, but in many cases the exact underlying mechanisms are elusive. A.FF">H.re we will discuss three notable examples of developmental.processes controlled by histone methylation in early embryonic systems: genomic imprinting, A.FF">H.X.gene expression and the regulation of pluripotency and differentiation programmes.A.FF">G.nomic imprinting.One of the earliest steps in development is the establishment of embryonic and extra-embryonic lineages. A.FF">G.nomic imprinting, which leads to mono-al.elic expression of a gene by silencing one of the parental.copies, is critical.for this stage, by ensuring proper dosage of each gene product. T.is process is especial.y important for genes on the X.chromosome, which exist in two copies in femal.s and one in mal.s. In femal.s, gene expression from one copy of the X.chromosome is silenced in cis by the long non-coding R.A.X.st, which is expressed from the otherwise silenced X.chromosome and recruits PR.2 to deposit gene-inactivating A.">A.FF">H.K.7me3 marks136. On the active chromosome, X.st itself is silenced by PR.2-mediated A.">A.FF">H.K.7me3 deposition137. Consequently, mice with mutated A.FF">F.A.A.FF">F.">E.d — which encodes the essential.PcA.FF">G.protein A.FF">F.A.A.FF">F.">E.D.— were defective in X.inactivation in the extra-embryonic lineages138 and in pre-implantation embryos139. A.FF">G.nes on other chromosomes are al.o imprinted, and the prevailing model has been that one al.ele is silenced by D.A.methylation1, with or without co-occurring A.">A.FF">H.K. methylation. D.A.methylation and A.">A.FF">H.K.7 methylation are mutual.y exclusive at one imprinted gene, R.sgrf1 (ref.140). A.FF">H.wever, A.">A.FF">H.K.7 methylation was recently shown to mediate imprinting at sites with low levels of D.A.methylation141, demonstrating the existence of two independent imprinting pathways (A.FF">F.g. 3a). A.proximately hal. of the active chromatin on the paternal.D.A.showed D.A.hypomethylation on the maternal.al.ele and contained A.">A.FF">H.K.7me3 tracts141. A.FF">G.nes imprinted by this mechanism included S./font>fmbt2 (ref.141,142), a PR.2 component required for the development of extra-embryonic lineages143. In the future, it will be important to understand how A.">A.FF">H.K.7-mediated imprinting contributes to organ development and lineage specification in the embryo.A.FF">F.g. 3: D.velopmental.processes regulated by histone methylation.a A.FF">G.nomic imprinting is mediated by both histone and D.A.methylation. Paternal.y expressed genes display undetectable or very low levels of repressive D.A.and A.">A.FF">H.K.7 methylation marks. T.e maternal.al.ele is silenced either by D.A.methylation, introduced by A.">D.A.methyltransferases (D.M.s), or, in regions of hypomethylated D.A. by tri-methylation of L.s27 of histone A.">A.FF">H. (A.">A.FF">H.K.7me3), introduced by the PR.2 complex. T.e predominant mechanism for the silencing of imprinted genes varies by the locus. b R.gulation of A.FF">H.X.genes by histone methylation. In embryonic stem cells (A.FF">F.A.A.FF">F.">E.Cs), histone tri-methylation at A.">A.FF">H.K.7 represses al. A.FF">H.X.genes. A. later stages of differentiation, early A.FF">H.X.genes are activated al.ng the anterior–posterior axis by removal.of A.">A.FF">H.K.7me3 and addition of A.">A.FF">H.K.me3. S./font>ubsequently, late A.FF">H.X.genes are activated in caudal.regions by a similar mechanism. In differentiated cells, A.FF">H.X.genes are again repressed by tri-methylation at A.">A.FF">H.K. and A.">A.FF">H.K.7. It is not known whether these methylation marks occur on the same or separate nucleosomes. c A.FF">F.A.A.FF">F.">E.fects of histone methylation regulators on A.FF">F.A.A.FF">F.">E.C self-renewal.and differentiation. A.though some regulators directly influence A.FF">F.A.A.FF">F.">E.C self-renewal.(S./font>A.FF">F.A.A.FF">F.">E.D.font style="background-color:#FFAAFF">B., W.font style="background-color:#A1DAEE">D.5, S./font>A.FF">F.A.A.FF">F.">E.D.A. A.FF">G.a), most affect the ability of A.FF">F.A.A.FF">F.">E.Cs to differentiate (as assessed by using embryoid body formation assays, which indicate the ability to form the three germ layers, or by various differentiation-inducing protocols (including those that direct A.FF">F.A.A.FF">F.">E.Cs towards a particular lineage)). In cases where different studies have indicated divergent roles, al. outcomes are listed. A.FF">F.r references to the relevant reports, see S./font>upplementary T.ble 3.A.FF">F.ll size image .R.gulation of A.FF">H.X.genes.One critical.and well-conserved role for histone methylation in development is in regulating expression of A.FF">H.X.genes. T.ese genes are arranged in linear arrays, where the position of the gene controls its spatiotemporal.expression patterns: genes at the distal.ends of the clusters are typical.y expressed later in development and are restricted to caudal.regions of the embryo144,145. Progressive activation of A.FF">H.X.genes corresponds to removal.of A.">A.FF">H.K.7me3 and appearance of A.">A.FF">H.K.me3 (ref.146). L.ter in development, A.FF">H.X.genes are silenced by methylation at A.">A.FF">H.K.7 and A.">A.FF">H.K. (ref.69) (A.FF">F.g. 3b). Interestingly, recent studies have suggested that A.FF">H.X.genes are briefly devoid of A.">A.FF">H.K.7 methylation after fertilization, but it is not known how they are kept inactive during this stage76.T.e effects of many genes discovered in the early D. melanogaster embryogenesis screens for developmental.defects were traced to their roles in regulating A.FF">H.X.gene expression. T.x mutant embryos showed reduced expression of the A.FF">H.X.gene Ultrabithorax (Ubx) concomitant with thoracic transformations. Overexpression of Ubx rescued these transformations84, leading to the conclusion that T.x was a A.FF">H.x activator84,147. PcA.FF">G.mutants, by contrast, led to expanded expression of A.FF">H.x genes in embryonic regions in which they are normal.y not expressed148,149, indicating a negative role for PcA.FF">G.in restricting A.FF">H.x expression to specific body regions149. Combined mutations of PcA.FF">G.and T.x restored some of the body patterning defects seen in the single mutants, suggesting that the two regulators act in opposite ways147. Of note, later studies uncovered more complex interactions between T.x and PcA.FF">G.group proteins, in which the double mutants failed to completely rescue A.FF">H.x expression in al. regions of the embryo. T.e wing discs of double mutants expressed Ubx at elevated levels comparable to those in single PcA.FF">G.mutants, leading the authors to conclude that T.x proteins act as ‘anti-repressors’ to suppress PcA.FF">G.mediated repression of gene expression, and that T.x is not otherwise required for A.FF">H.x gene activation in al. contexts150. A.though the biochemical.functions of T.x and PcA.FF">G.proteins were not understood at the time, these studies have demonstrated essential.roles for both gene-activating (A.">A.FF">H.K.) and gene-repressing (A.">A.FF">H.K.7) methylation in ensuring that appropriate A.FF">H.x genes are expressed in each body segment.D.spite the variable effects of different types of histone methylation on mammal.an development, their effects on A.FF">H.X.gene expression typical.y al.gn with the activating or repressive features of each mark. M.use embryos lacking the A.">A.FF">H.K. methyltransferase M.L., the homologue of D. melanogaster T.x, displayed embryonic lethal.ty between A.FF">F.A.A.FF">F.">E.0.5 and A.FF">F.A.A.FF">F.">E.5 (refs104,106,151), with defects in body patterning — abnormal.branchial.arches, mixed rostral.caudal.neural.patterning152 and caudal.zation of A.FF">H.x gene expression153 — similar to its effects in flies154. K.ockout of L.font style="background-color:#0000CC">S./font>D., the A.">A.FF">H.K. demethylase, showed effects opposite to those of M.L. at the molecular level, leading to premature or excessive expression of A.FF">H.xb7 and A.FF">H.xd8 (ref.155) and embryonic lethal.ty at A.FF">F.A.A.FF">F.">E.A.FF">F.A.A.FF">F.">E.C0">A.FF">F.A.A.FF">F.">E..5 (ref.95). T.us, it is clear that a bal.nce of histone methylation and demethylation is al.o required for proper A.FF">H.x gene expression and successful embryogenesis in mammal.. A.FF">H.wever, in mammal., more complex roles for A.">A.FF">H.K. methylation have been seen, owing to the presence of six A.">A.FF">H.K. methyltransferases: S./font>A.FF">F.A.A.FF">F.">E.D.A. S./font>A.FF">F.A.A.FF">F.">E.D.B.and M.L.M.L.. T.ese enzymes were individual.y required at various stages of embryogenesis, resulting in lethal.ty between A.FF">F.A.A.FF">F.">E. and A.FF">F.A.A.FF">F.">E.5 in the individual.knockouts99,104,105,106,151,156,157,158. T.eir distinct embryonic phenotypes supported their non-overlapping methylation patterns, including global.A.">A.FF">H.K. tri-methylation (S./font>A.FF">F.A.A.FF">F.">E.D.A.and S./font>A.FF">F.A.A.FF">F.">E.D.B.59), promoter-specific methylation (M.L. (ref.160)) and mono-methylation at enhancers (M.L. (ref.161)). Curr.ntly, the detailed mechanisms by which these locus-specific methylations ultimately govern A.FF">H.X.genes and other developmental.regulators remain poorly understood. A. in D. melanogaster, methylation dynamics at A.">A.FF">H.K.7 are al.o required in mammal. for successful embryogenesis and A.FF">H.X.gene regulation. A.cordingly, mutations in the components of the PR.2 complex — which is the mammal.an PcA.FF">G.homologue, consisting of the methyltransferases A.FF">F.A.A.FF">F.">E.A.FF">H. and A.FF">F.A.A.FF">F.">E.A.FF">H., al.ng with the other regulatory components B.I1, A.FF">F.A.A.FF">F.">E.D. S./font>UZ.2, R.font style="background-color:#FFAAFF">B.font style="background-color:#FFAAFF">A.46 and R.font style="background-color:#FFAAFF">B.font style="background-color:#FFAAFF">A.48 (ref.35) — resulted in body-patterning defects in mice. A.FF">Conditional./font> knockout of A.FF">F.A.A.FF">F.">E.h2 in specific cell types later in development — to circumvent early embryonic lethal.ty in A.FF">F.A.A.FF">F.">E.h2-null embryos162,163 by A.FF">F.A.A.FF">F.">E.A.FF">F.A.A.FF">F.">E.C0">A.FF">F.A.A.FF">F.">E..5 (before body patterning) — led to mispatterned (anteriorized)164 or general.y increased165 expression of A.FF">H.x genes. B.th A.FF">F.A.A.FF">F.">E.d and S./font>uz12 knockout mutations were lethal.by A.FF">F.A.A.FF">F.">E..5 and A.FF">F.A.A.FF">F.">E.A.FF">F.A.A.FF">F.">E.C0">A.FF">F.A.A.FF">F.">E..5, respectively, with major body-patterning defects such as reduced mesoderm and misexpression of key developmental.regulators (brachyury, A.FF">F.A.A.FF">F.">E.x1)166,167,168. B.i1 knockout mice, despite clear al.erations in the proper establishment of A.FF">H.x gene expression boundaries169, were viable until birth, but died shortly afterwards with impaired haematopoiesis and subtle skeletal. neurological.and haematopoietic defects113. T.ese variable results suggest that PR.2 subunits may perform some functions independently of their roles in the methyltransferase complex, and/or that the complex may retain some functions during development in the absence of some subunits. A. expected, the A.">A.FF">H.K.7 demethylases K.font style="background-color:#A1DAEE">D.6A.and K.font style="background-color:#A1DAEE">D.6B.displayed effects opposite to PR.2 on A.FF">H.x gene expression170. In zebrafish, loss of K.font style="background-color:#A1DAEE">D.6A.resulted in posterior patterning defects and reduced expression of multiple A.FF">H.x genes119. In mice, femal. embryos lacking K.font style="background-color:#A1DAEE">D.6A.died before birth with defects in cardiac development and neural.tube closure; however, the requirement for K.font style="background-color:#A1DAEE">D.6A.for unperturbed development was partial.y compensated for in mal.s by K.font style="background-color:#A1DAEE">D.6C (al.o known as UT.font style="background-color:#FFAAFF">Y.171, a catal.tical.y inactive homologue of the enzyme present on the Y.chromosome119,172, which al.owed survival.until birth. T.e critical.roles of K.font style="background-color:#A1DAEE">D.6A.may involve the recruitment of other chromatin regulators instead of direct A.">A.FF">H.K.7 demethylation (B.x 1), a function that K.font style="background-color:#A1DAEE">D.6C is expected to be able to fulfil. L.ss of the catal.tic activity of K.font style="background-color:#A1DAEE">D.6B.delayed expression of posterior A.FF">H.x genes and led to the anteriorization of A.FF">H.x boundaries, with resulting skeletal.abnormal.ties; however, the embryos were viable until birth, al.eit with postnatal.loss of viability173. Overal., the distinct phenotypes resulting from loss of biochemical.y equival.nt A.">A.FF">H.K.7 methylation regulators suggest that they likely have distinct genomic targets, and therefore act on non-overlapping sets of essential.developmental.genes.R.gulation of cell fate and specification.T.e embryonic defects arising at the onset of organogenesis from aberrant histone methylation suggest that histone methylation potently affects cell fate decisions. T. circumvent the obstacles of embryonic lethal.ty and to study cell fate decisions directly, many studies have anal.sed the self-renewal.or differentiation of A.FF">F.A.A.FF">F.">E.Cs in vitro. A. emerging theme from these studies is that the regulators that are required early in development have roles in maintaining A.FF">F.A.A.FF">F.">E.C pluripotency, whereas those acting during organogenesis or later tend to suppress or enhance A.FF">F.A.A.FF">F.">E.C differentiation (A.FF">F.g. 3c; see al.o A.FF">F.g. 2). A.FF">F.r example, S./font>A.FF">F.A.A.FF">F.">E.D.font style="background-color:#FFAAFF">B., an A.">A.FF">H.K. methyltransferase that shows the earliest requirement during embryogenesis, was required for the maintenance of pluripotency in A.FF">F.A.A.FF">F.">E.Cs99. B. contrast, regulators that are required later during embryonic development, such as the methyltransferases M.L. (refs174,175), M.L. (refs174,176,177), S./font>A.FF">F.A.A.FF">F.">E.D.A.78, A.FF">G.a179 and PR.2 (ref.180), or demethylases such as K.font style="background-color:#A1DAEE">D.6A.and K.font style="background-color:#A1DAEE">D.6B.81, were largely not required for the maintenance of pluripotency, but their loss compromised differentiation in vitro174,177,179,182. L.ss of the demethylase L.font style="background-color:#0000CC">S./font>D. (ref.183) or K.font style="background-color:#A1DAEE">D.3A.84 promoted A.FF">F.A.A.FF">F.">E.C differentiation, in accordance with their antagonistic relationships to the A.">A.FF">H.K. and A.">A.FF">H.K. methyltransferases. T.ese results suggest that the stage at which a regulator acts during embryogenesis may be inferred from in vitro models of A.FF">F.A.A.FF">F.">E.C maintenance and differentiation. Notably, however, not al. methylation regulators showed this direct correspondence between embryonic and A.FF">F.A.A.FF">F.">E.C phenotypes. A.FF">F.r example, PR.font style="background-color:#A1DAEE">M.4 (ref.100) supported pluripotency maintenance in human and mouse A.FF">F.A.A.FF">F.">E.Cs, likely by directly promoting A.FF">F.A.A.FF">F.">E.C self-renewal. rather than by regulating pluripotency versus differentiation programmes as such100,185,186. A.study separate from ref.178 reported a similar role for S./font>A.FF">F.A.A.FF">F.">E.D.A.87 in supporting A.FF">F.A.A.FF">F.">E.C pluripotency. A.so included in this group are regulators that promote A.FF">F.A.A.FF">F.">E.C differentiation when they are lost (for example, L.font style="background-color:#0000CC">S./font>D. (ref.183)). T.ese regulators shift the cell fate decision away from self-renewal. and thus appear to be required for the maintenance of pluripotency via affecting differentiation programmes, which recapitulates their embryonic roles. K.font style="background-color:#A1DAEE">D.4C, whose embryonic phenotype has not been investigated, was reported in separate studies to both promote188 and inhibit184 differentiation, a discrepancy that has not been resolved. T.us, al.hough A.FF">F.A.A.FF">F.">E.C-based studies have been very powerful in elucidating the developmental.functions of chromatin regulators, such exceptions, al.ng with discrepancies in histone methylation patterns between A.FF">F.A.A.FF">F.">E.Cs and pre-implantation embryos76, highlight the imperfect correspondence between in vitro and in vivo studies.A.other complication in studying the role of histone methylation in cell fate determination stems from the fact that individual.histone marks and their regulatory enzymes often show distinct effects on A.FF">F.A.A.FF">F.">E.C differentiation towards different lineages. A.FF">F.r example, M.L. loss led to deficits in differentiation towards endoderm, an increase in mesodermal./font> markers, but relatively few effects on differentiation into embryoid bodies and ectoderm189. A. another example, PR.font style="background-color:#A1DAEE">M.6 overexpression induced endodermal./font> markers but had varying effects on mesodermal./font> and ectodermal.markers, whereas its depletion led to varying increases in markers of al. three lineages190. A.FF">F.rthermore, these effects on differentiation due to changes in the expression of methylation regulators in many cases do not correspond to the effects observed for other related and/or seemingly functional.y equival.nt enzymes. A.FF">F.r example, both K.font style="background-color:#A1DAEE">D.4C and K.font style="background-color:#A1DAEE">D.3A.remove repressive A.">A.FF">H.K. methylations (tri-methylation and di-methylation, respectively), yet the gene expression programmes in knockout A.FF">F.A.A.FF">F.">E.Cs showed distinct differences, which corresponded to the differentiation towards different lineages: endodermal./font> in K.m4c knockout cells, and mesodermal./font> in K.m3a knockout cells184. In addition, an independent study showed no deficits at al. in self-renewal.of K.m3a knockout A.FF">F.A.A.FF">F.">E.Cs191. T.ese differences may arise from local.zation of the K.font style="background-color:#A1DAEE">D.4C and K.font style="background-color:#A1DAEE">D.3A.substrates to different loci, with A.">A.FF">H.K.me3 local.zing to pericentric heterochromatin and A.">A.FF">H.K.me2 local.zing to euchromatin13,15. T.e details of how these distinct marks lead to differences in lineage specification remain to be elucidated. S./font>imilarly, S./font>A.FF">F.A.A.FF">F.">E.D.A.and M.L. both methylate A.">A.FF">H.K., but only S./font>A.FF">F.A.A.FF">F.">E.D.A.appeared to promote methylation during A.FF">F.A.A.FF">F.">E.C differentiation, in part by regulating the A.FF">H.xa locus178 via the methylation of two enhancers187. T.e loss of W.font style="background-color:#A1DAEE">D.5, which forms a complex with S./font>A.FF">F.A.A.FF">F.">E.1D.A.(and S./font>A.FF">F.A.A.FF">F.">E.1D.B., showed effects opposite to those of M.L. loss, leading to impaired A.FF">F.A.A.FF">F.">E.C self-renewal.92 in contrast to impaired differentiation. A.FF">F.nal.y, M.L. was required for establishing methylation at bival.nt genes in A.FF">F.A.A.FF">F.">E.Cs, whereas the highly related M.L. showed a weaker A.D.font style="background-color:#FFAAFF">A.E">requirement174. A.though the finding is in contrast to the late-stage lethal.ty of M.L. knockout embryos (A.FF">F.g. 2a), the involvement of M.L. in promoting bival.nt methylation marks in A.FF">F.A.A.FF">F.">E.Cs is consistent with observations that embryos lacking maternal.M.L. arrest by the two-cell stage98, whereas M.L. is required for development only much later, at the onset of haematopoiesis104,151. In summary, owing to these complex effects of methylation marks and the enzymes that regulate them, a description of a unifying developmental.histone code has been so far inaccessible.R.levance to human genetic disorders.A.FF">H.man disease-associated mutations in genes encoding histone methylation regulators (T.ble 2) have highlighted the importance of dynamic regulation of histone methylation in skeletal.and neurodevelopment. M.tations in the A.">A.FF">H.K. methyltransferase genes S./font>A.FF">F.A.A.FF">F.">E.D.B.and M.L.–4 have al. been implicated in syndromes characterized by skeletal.and facial.abnormal.ties and intellectual.disability, typical.y involving reduced body size and microcephal.193,194,195,196,197,198,199. M.tations in the A.">A.FF">H.K. demethylase-encoding genes K.font style="background-color:#A1DAEE">D.5C200,201,202 and L.font style="background-color:#0000CC">S./font>D. (refs203,204) or in the gene encoding the L.font style="background-color:#0000CC">S./font>D. binding partner PA.FF">H. finger protein 21A.(B.font style="background-color:#FFA.FF">H.80; al.o known as PA.FF">H.font style="background-color:#FFA.FF">F.1A.52,205 resulted in similar syndromes, characterized by intellectual.disability and skeletal.defects. Notably, mutations in both M.L. and its antagonist L.font style="background-color:#0000CC">S./font>D. have been associated with K.buki syndrome197,198,203,204, reveal.ng that opposing activities at a molecular level can cause similar outcomes at an organismal.level. D.namic methylation at A.">A.FF">H.K. is al.o required for proper skeletal.and neural.development. M.tations in both the A.">A.FF">H.K. demethylase-encoding PA.FF">H.font style="background-color:#FFA.FF">F. (refs206,207) and the methyltransferase-encoding A.FF">G.P were associated with craniofacial.defects and intellectual.disability in both humans208,209,210,211 and animal.models212,213.T.ble 2 A.FF">H.stone methylation regulators associated with inherited genetic disorders in humansA.FF">F.ll size table In contrast to the above mutations that cause reduced skeletal.and brain size, mutations in other histone methylation regulators can lead to overgrowth syndromes. A.FF">F.r example, mutations in A.FF">F.A.A.FF">F.">E.A.FF">H. and NS./font>D. — which encode A.">A.FF">H.K.7 and A.">A.FF">H.K.6 methyltransferases, respectively — lead to overgrowth pathologies typical.of W.aver, S./font>otos, and B.ckwith–W.edemann syndromes214,215,216,217. A.FF">H.wever, mutations in NS./font>D., another A.">A.FF">H.K.6 methyltransferase-encoding gene, led to growth delays, indicating non-redundant, or even opposing, roles for these related enzymes. B.yond the differences between the enzymes, it should al.o be considered that germline and somatic mutations can result in divergent phenotypes. T.is seems to be the case for A.FF">F.A.A.FF">F.">E.A.FF">H. and NS./font>D., which are often overexpressed in cancers218,219,220, despite their loss of function in embryos being associated with overgrowth as discussed above, and even in cancer predisposition221.In the only known example of a clinical.phenotype associated with genetic disruption of A.g methyltransferases, loss-of-function mutations in PR.font style="background-color:#A1DAEE">M.7 were associated with mild intellectual.disability al.ng with obesity and poor development of bones222. A.recent large-scal. sequencing study showed many mutations in histone methyltransferases and demethylases linked to developmental.delays223, suggesting that the full scope of involvement of these enzymes in embryonic and postnatal.development in humans has yet to be explored.A.al.ses of disease-associated mutations in histone methylation regulators have provided limited insights into the molecular mechanisms underlying the associated pathologies. M.ny of the reported mutations disrupt or reduce the activity of the corresponding enzymes193,194,197,205,214,224, interfere with their binding to complex members or to D.A.94,214, or reduce their expression at the R.A.or protein level205,225. It is not known whether truncated or catal.tical.y inactive forms of the mutant proteins have functional.roles, al.hough the variations in disease presentation caused by different mutations (for example, in NS./font>D. (refs215,216,217)) suggest that these mutant proteins may have non-catal.tic effects. In some cases, phenotypes have been linked to misregulation of a few critical.genes. A.FF">F.r example, M.L. mutations led to reduced expression of intellectual.disability-associated genes such as T.font style="background-color:#FFA.FF">H.P1 and T.R. (ref.194). A.mouse model of K.eefstra syndrome, driven by A.FF">G.p mutation, showed increased rather than decreased A.">A.FF">H.K.me3, as would be expected on the basis of the function of A.FF">G.P as an A.">A.FF">H.K. methyltransferase. It was then proposed that a concomitant reduction in expression of protocadherins underlies some of the phenotypes of A.FF">G.p mutants213. A.though mouse knockouts have served as faithful models of disease in some cases213,226, many human genetic disorders are not recapitulated in mouse models. A.FF">F.r example, the loss of A.">A.FF">H.K. methyltransferases in mouse results in haematopoietic rather than skeletal.or neural.disorders, al.hough one report showed that heterozygous M.l4 knockouts display smal.er body size, similar to human patients with M.L.mutations198. A.FF">F.rther characterization of the functions of histone methylation regulators in various organs and cell types in humans — for example, using organoid systems — may begin to uncover the molecular mechanisms by which their deregulation causes disease.Concluding remarks.S./font>tudies in embryonic model systems laid the foundational.basis for the field of epigenetics five decades ago, yet many mysteries still remain regarding the roles and regulation of epigenetic marks during embryonic development. It is clear that histone methylations have important functions throughout development in nearly al. cell and tissue types. K.y roles for histone methylation in promoting body patterning via A.FF">H.X.gene regulation are well-conserved across species, and histone methylations additional.y regulate other developmental.gene networks. A.FF">H.wever, different chromatin regulators often have distinct roles during development even when acting on the same modification; thus, obtaining a full understanding of their functions will require integrating their effects at different genomic loci — for example, promoters, enhancers, heterochromatin and individual.genes — and in different cellular contexts with the phenotypic effects on development. A.al.ses of chromatin in specific embryonic tissues have begun to shed light on some of these differences. In addition, A.FF">F.A.A.FF">F.">E.Cs have provided powerful al.ernative models for studying the effects of chromatin regulators on maintaining pluripotency and promoting differentiation al.ng diverse lineages.A.though genomic studies have defined overarching histone methylation patterns during development, direct causal.relationships between methylation events and the formation of embryonic structures or mature organs have been difficult to define. In many cases, methylation has critical.effects at multiple genetic loci, making classical.reverse genetic studies focused on the regulation of individual.genes difficult to interpret. A.FF">F.rthermore, bulk anal.ses can mask the heterogeneity of methylation patterns and their outcomes observed across cell types and developmental.stages. W.ereas imaging anal.sis can provide useful single-cell information, further advances in molecular techniques will be needed in order to define how methylation patterns influence gene expression in a tissue-specific manner. D.termining the relative contributions of promoter and enhancer regulation by methylation, as well as how histone methylations interact with other aspects of chromatin structure, such as nucleosome positioning and 3D.genome architecture, will help to further define the molecular mechanisms by which histone methylations operate in development. S./font>tudies of early embryos in mouse and zebrafish have suggested the existence of unique mechanisms of gene regulation. A.FF">F.r example, zygotic transcription in zebrafish is suppressed despite the presence of activating marks at some genes67, and mouse A.FF">H.x genes transiently lose repressive A.">A.FF">H.K.7me3 marks after fertilization yet maintain gene silencing76. D.termining how these al.ernative modes of gene repression operate and how they interact with histone methylations will be important for fully understanding the regulatory mechanisms of gene expression in embryos. A.FF">F.nal.y, al.hough much progress has been made in understanding the roles of histone L.s methylation, our understanding of histone A.g methylation lags behind. Comprehensive mapping of A.g methylation across developmental.stages and tissue types will be an essential.first step towards understanding its role in development.Overal., dissecting the roles of various histone methylation regulators at each stage of embryogenesis, using conventional.genetics combined with conditional.knockout studies and anal.ses of A.FF">F.A.A.FF">F.">E.Cs, will help us understand the overlapping and unique features of human genetic disorders involving aberrant histone methylation, and eventual.y will al.ow the developmental.histone code to be cracked. R.ferences.1. A.FF">G.eenberg, M. & B.urc’his, D. T.e diverse roles of D.A.methylation in mammal.an development and disease. Nat. R.v. M.l. Cell B.ol. In the press.2. S./font>trahl, B. D. & A.lis, C. D. T.e language of coval.nt histone modifications. Nature 403, 41–45 (2000).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.3. B.rski, A. et al. A.FF">H.gh-resolution profiling of histone methylations in the human genome. Cell 129, 823–837 (2007).CA.font style="background-color:#0000CC">S./font>.A.ticle. A.FF">G.ogle S./font>cholar.4. B.rnstein, B. A.FF">F.A.A.FF">F.">E. et al. A.bival.nt chromatin structure marks key developmental.genes in embryonic stem cells. Cell 125, 315–326 (2006). A. early paper demonstrating bival.nt histone methylation marks and their functions. CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.5. M.kkelsen, T. S./font>. et al. A.FF">G.nome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448, 553–560 (2007).CA.font style="background-color:#0000CC">S./font>.A.ticle.PubM.d.PubM.d Central. A.FF">G.ogle S./font>cholar.6. van A.ensbergen, J. et al./font>. D.repression of Polycomb targets during pancreatic organogenesis al.ows insulin-producing beta-cells to adopt a neural.gene activity program. A.FF">G.nome R.s. 20, 722–732 (2010).PubM.d.PubM.d Central.A.ticle.CA.font style="background-color:#0000CC">S./font>. A.FF">G.ogle S./font>cholar.7. B.rnstein, B. A.FF">F.A.A.FF">F.">E. et al. M.thylation of histone A.">A.FF">H. L.s 4 in coding regions of active genes. Proc. Natl A.ad. S./font>ci. US./font>A.99, 8695–8700 (2002).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.8. B.rnstein, B. A.FF">F.A.A.FF">F.">E. et al. A.FF">G.nomic maps and comparative anal.sis of histone modifications in human and mouse. Cell 120, 169–181 (2005).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.9. B.nnister, A. J. et al./font>. S./font>patial.distribution of di- and tri-methyl lysine 36 of histone A.">A.FF">H. at active genes. J. B.ol. Chem. 280, 17732–17736 (2005).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.10. W.ng, Z. et al. Combinatorial.patterns of histone acetylations and methylations in the human genome. Nat. A.FF">G.net. 40, 897–903 (2008).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.11. A.FF">H.intzman, N. D. et al. D.stinct and predictive chromatin signatures of transcriptional.promoters and enhancers in the human genome. Nat. A.FF">G.net. 39, 311–318 (2007).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.12. T.ojer, P. & R.inberg, D. A.FF">F.cultative heterochromatin: is there a distinctive molecular signature? M.l. Cell 28, 1–13 (2007).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.13. Peters, A.FF">F.A.A.FF">F.">A. A.FF">H. et al./font>. Partitioning and plasticity of repressive histone methylation states in mammal.an chromatin. M.l. Cell 12, 1577–1589 (2003).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.14. R.a, S./font>. et al. R.gulation of chromatin structure by site-specific histone A.">A.FF">H. methyltransferases. Nature 406, 593–599 (2000). A.FF">F.rst demonstration of the histone methyltransferase activity of the S./font>A.FF">F.A.A.FF">F.">E. domain. CA.font style="background-color:#0000CC">S./font>.A.ticle. A.FF">G.ogle S./font>cholar.15. R.ce, J. C. et al. A.FF">H.stone methyltransferases direct different degrees of methylation to define distinct chromatin domains. M.l. Cell 12, 1591–1598 (2003).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.16. L.n, W. J., A.FF">G.ry, J. D., Y.ng, M. C., Clarke, S./font>. & A.FF">H.rschman, A.FF">H. R. T.e mammal.an immediate-early T.S./font>21 protein and the leukemia-associated B.A.FF">G. protein interact with a protein-arginine N-methyltransferase. J. B.ol. Chem. 271, 15034–15044 (1996).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.17. T.ng, J. et al./font>. PR.font style="background-color:#A1DAEE">M.1 is the predominant type I protein arginine methyltransferase in mammal.an cells. J. B.ol. Chem. 275, 7723–7730 (2000).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.18. A.FF">G.ccione, A.FF">F.A.A.FF">F.">E. & R.chard, S./font>. T.e regulation, functions and clinical.relevance of arginine methylation. Nat. R.v. M.l. Cell B.ol. https://doi.org/10.1038/s41580-019-0155-x (2019).19. M.jumder, S./font>. et al. M.thylation of histone A.">A.FF">H. and A.">A.FF">H. by PR.font style="background-color:#A1DAEE">M.5 regulates ribosomal.R.A.gene transcription. J. Cell. B.ochem. 109, 553–563 (2010).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central. A.FF">G.ogle S./font>cholar.20. D.cwag, C. S./font>., Ohkawa, Y., Pal. S./font>., S./font>if, S./font>. & Imbal.ano, A. N. T.e protein arginine methyltransferase Prmt5 is required for myogenesis because it facilitates A.P-dependent chromatin remodeling. M.l. Cell. B.ol. 27, 384–394 (2007).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.21. A.FF">G.rardot, M. et al. PR.font style="background-color:#A1DAEE">M.5-mediated histone A.">A.FF">H. arginine-3 symmetrical.dimethylation marks chromatin at A.FF">G.+ C-rich regions of the mouse genome. Nucleic A.ids R.s. 42, 235–248 (2014).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.22. A.FF">F.A.A.FF">F.">E.ger, A.FF">G., L.ang, A.FF">G., A.aricio, A. & Jones, P. A. A.FF">F.A.A.FF">F.">E.igenetics in human disease and prospects for epigenetic therapy. Nature 429, 457–463 (2004).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.23. D.xon, J. R. et al. T.pological.domains in mammal.an genomes identified by anal.sis of chromatin interactions. Nature 485, 376–380 (2012).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.24. L.eberman-A.den, A.FF">F.A.A.FF">F.">E. et al. Comprehensive mapping of long-range interactions reveal. folding principles of the human genome. S./font>cience 326, 289–293 (2009).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.25. Z.ao, Y. & A.FF">G.rcia, A.FF">B. A. Comprehensive catal.g of currently documented histone modifications. Cold S./font>pring A.FF">A.FF">H.rb. Perspect. B.ol. 7, a025064 (2015).PubM.d.PubM.d Central.A.ticle.CA.font style="background-color:#0000CC">S./font>. A.FF">G.ogle S./font>cholar.26. Y.ng, A.FF">L. et al. M.lecular cloning of A.FF">F.A.A.FF">F.">E.A.FF">F.A.A.FF">F.">E., a novel histone A.">A.FF">H.-specific methyltransferase that interacts with A.FF">F.A.A.FF">F.">E.A.FF">G.transcription factor. Oncogene 21, 148–152 (2002).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.27. T.chibana, M., S./font>ugimoto, K., A.FF">F.kushima, T. & S./font>hinkai, Y. S./font>et domain-containing protein, A.FF">G.a, is a novel lysine-preferring mammal.an histone methyltransferase with hyperactivity and specific selectivity to lysines 9 and 27 of histone A.">A.FF">H.. J. B.ol. Chem. 276, 25309–25317 (2001).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.28. W.ng, A.FF">H. et al. Purification and functional.characterization of a histone A.">A.FF">H.-lysine 4-specific methyltransferase. M.l. Cell 8, 1207–1217 (2001).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.29. Nishioka, K. et al. S./font>et9, a novel histone A.">A.FF">H. methyltransferase that facilitates transcription by precluding histone tail modifications required for heterochromatin formation. A.FF">G.nes D.v. 16, 479–489 (2002).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.30. Nishioka, K. et al. PR.S./font>et7 is a nucleosome-specific methyltransferase that modifies lysine 20 of histone A.">A.FF">H. and is associated with silent chromatin. M.l. Cell 9, 1201–1213 (2002).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.31. A.FF">F.ng, Q. et al./font>. M.thylation of A.">A.FF">H.-lysine 79 is mediated by a new family of A.FF">H.T.ses without a S./font>A.FF">F.A.A.FF">F.">E. domain. Curr. B.ol. 12, 1052–1058 (2002).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.32. Ng, A.FF">H. A.FF">H. et al. L.sine methylation within the globular domain of histone A.">A.FF">H. by D.t1 is important for telomeric silencing and S./font>ir protein association. A.FF">G.nes D.v. 16, 1518–1527 (2002).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.33. van L.euwen, A.FF">F., A.FF">G.fken, P. R. & A.FF">G.ttschling, D. A.FF">F.A.A.FF">F.">E. D.t1p modulates silencing in yeast by methylation of the nucleosome core. Cell 109, 745–756 (2002).PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.34. S./font>hilatifard, A. M.lecular implementation and physiological.roles for histone A.">A.FF">H. lysine 4 (A.">A.FF">H.K.) methylation. Curr. Opin. Cell B.ol. 20, 341–348 (2008).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.35. K.zmichev, A., Nishioka, K., A.FF">F.A.A.FF">F.">E.djument-B.omage, A.FF">H., T.mpst, P. & R.inberg, D. A.FF">H.stone methyltransferase activity associated with a human multiprotein complex containing the enhancer of Z.ste protein. A.FF">G.nes D.v. 16, 2893–2905 (2002).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.36. Cao, R. et al. R.le of histone A.">A.FF">H. lysine 27 methylation in Polycomb-group silencing. S./font>cience 298, 1039–1043 (2002).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.37. M.ller, J. et al./font>. A.FF">H.stone methyltransferase activity of a D.osophila Polycomb group repressor complex. Cell 111, 197–208 (2002).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.38. L.e, T. I. et al. Control of developmental.regulators by Polycomb in human embryonic stem cells. Cell 125, 301–313 (2006).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.39. Peters, A.FF">F.A.A.FF">F.">A. A.FF">H. et al./font>. L.ss of the S./font>uv39h histone methyltransferases impairs mammal.an heterochromatin and genome stability. Cell 107, 323–337 (2001).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.40. Chen, D. et al. R.gulation of transcription by a protein methyltransferase. S./font>cience 284, 2174–2177 (1999).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.41. W.ng, M., X., R. M. & T.ompson, P. R. S./font>ubstrate specificity, processivity, and kinetic mechanism of protein arginine methyltransferase 5. B.ochemistry 52, 5430–5440 (2013).PubM.d.A.ticle.CA.font style="background-color:#0000CC">S./font>. A.FF">G.ogle S./font>cholar.42. M.randa, T. B., M.randa, M., A.FF">F.ankel, A. & Clarke, S./font>. PR.font style="background-color:#A1DAEE">M.7 is a member of the protein arginine methyltransferase family with a distinct substrate specificity. J. B.ol. Chem. 279, 22902–22907 (2004).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.43. L.e, J. A.FF">H. et al. PR.font style="background-color:#A1DAEE">M.7, a new protein arginine methyltransferase that synthesizes symmetric dimethylarginine. J. B.ol. Chem. 280, 3656–3664 (2005).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.44. Z.rita-L.pez, C. I., S./font>andberg, T., A.FF">K.lly, R. & Clarke, S./font>. A.FF">G. A.FF">H.man protein arginine methyltransferase 7 (PR.font style="background-color:#A1DAEE">M.7) is a type III enzyme forming omega-NA.FF">G.monomethylated arginine residues. J. B.ol. Chem. 287, 7859–7870 (2012).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.45. S./font>hi, Y. et al. A.FF">H.stone demethylation mediated by the nuclear amine oxidase homolog L.font style="background-color:#0000CC">S./font>D.. Cell 119, 941–953 (2004). A.FF">F.rst demonstration of enzymatic demethylase activity. CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.46. M.tzger, A.FF">F.A.A.FF">F.">E. et al. L.font style="background-color:#0000CC">S./font>D. demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 437, 436–439 (2005).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.47. Cloos, P. A. et al. T.e putative oncogene A.FF">G.S./font>C1 demethylates tri- and dimethylated lysine 9 on histone A.">A.FF">H.. Nature 442, 307–311 (2006).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.48. K.ose, R. J. et al./font>. T.e transcriptional.repressor JA.FF">H.M.A.demethylates trimethyl histone A.">A.FF">H. lysine 9 and lysine 36. Nature 442, 312–316 (2006).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.49. T.ukada, Y. et al. A.FF">H.stone demethylation by a family of JmjC domain-containing proteins. Nature 439, 811–816 (2006).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.50. W.etstine, J. R. et al. R.versal.of histone lysine trimethylation by the JM.D. family of histone demethylases. Cell 125, 467–481 (2006).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.51. A.FF">F.anci, A.FF">G., Ciotta, A. & A.tucci, L. T.e Jumonji family: past, present and future of histone demethylases in cancer. B.omol. Concepts 5, 209–224 (2014).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.52. L.n, A.FF">F. et al. R.cognition of unmethylated histone A.">A.FF">H. lysine 4 links B.font style="background-color:#FFA.FF">H.80 to L.font style="background-color:#0000CC">S./font>D.-mediated gene repression. Nature 448, 718–722 (2007).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.53. L., A.FF">H. et al. M.lecular basis for site-specific read-out of histone A.">A.FF">H.K.me3 by the B.T.font style="background-color:#FFA.FF">F.PA.FF">H. finger of NUR.font style="background-color:#FFA.FF">F. Nature 442, 91–95 (2006).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.54. Pena, P. V. et al. M.lecular mechanism of histone A.">A.FF">H.K.me3 recognition by plant homeodomain of INA.FF">G.. Nature 442, 100–103 (2006).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.55. S./font>hi, X. et al. INA.FF">G. PA.FF">H. domain links histone A.">A.FF">H. lysine 4 methylation to active gene repression. Nature 442, 96–99 (2006).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.56. W.socka, J. et al./font>. A.PA.FF">H. finger of NUR.font style="background-color:#FFA.FF">F.couples histone A.">A.FF">H. lysine 4 trimethylation with chromatin remodelling. Nature 442, 86–90 (2006).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.57. Chen, C., Nott, T. J., Jin, J. & Pawson, T. D.ciphering arginine methylation: T.dor tells the tal.. Nat. R.v. M.l. Cell B.ol. 12, 629–642 (2011).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.58. T.omson, J. P. et al./font>. CpA.FF">G.islands influence chromatin structure via the CpA.FF">G.binding protein Cfp1. Nature 464, 1082–1086 (2010). T.is paper shows how crosstal. is established between D.A.methylation and A.">A.FF">H.K. methylation deposited by the S./font>A.FF">F.A.A.FF">F.">E.D. complex. CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.59. L.ue, K. et al. T.e multidomain protein B.pf1 binds histones and is required for A.FF">H.x gene expression and segmental.identity. D.velopment 135, 1935–1946 (2008).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.60. Qiu, Y. et al. Combinatorial.readout of unmodified A.">A.FF">H.R. and acetylated A.">A.FF">H.K.4 by the tandem PA.FF">H. finger of M.Z.reveal. a regulatory mechanism for A.FF">H.X.font style="background-color:#FFAAFF">A. transcription. A.FF">G.nes D.v. 26, 1376–1391 (2012).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.61. V.zzoli, A. et al. M.lecular basis of histone A.">A.FF">H.K.6me3 recognition by the PW.P domain of B.pf1. Nat. S./font>truct. M.l. B.ol. 17, 617–619 (2010).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.62. R.mon-M.iques, S./font>. et al. T.e plant homeodomain finger of R.font style="background-color:#FFAAFF">A.font style="background-color:#FFA.FF">G. recognizes histone A.">A.FF">H. methylated at both lysine-4 and arginine-2. Proc. Natl A.ad. S./font>ci. US./font>A.104, 18993–18998 (2007).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.63. M.tthews, A. A.FF">G. et al. R.font style="background-color:#FFAAFF">A.font style="background-color:#FFA.FF">G. PA.FF">H. finger couples histone A.">A.FF">H. lysine 4 trimethylation with V.D.J recombination. Nature 450, 1106–1110 (2007).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.64. K.m, J. D. et al. Proper activity of histone A.">A.FF">H. lysine 4 (A.">A.FF">H.K.) methyltransferase is required for morphogenesis during zebrafish cardiogenesis. M.l. Cells 38, 580–586 (2015).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.65. L.e, J. et al./font>. S./font>A.FF">F.A.A.FF">F.">E.D. drives cardiac lineage commitment through stage-specific transcriptional.activation. Cell S./font>tem Cell 22, 428–444 (2018).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.66. Z.ao, X. D. et al. W.ole-genome mapping of histone A.">A.FF">H. L.s4 and 27 trimethylations reveal. distinct genomic compartments in human embryonic stem cells. Cell S./font>tem Cell 1, 286–298 (2007).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.67. L.ndeman, L. C. et al./font>. Prepatterning of developmental.gene expression by modified histones before zygotic genome activation. D.v. Cell 21, 993–1004 (2011). D.monstration that inactive genes can be ‘pre-marked’ for expression later in development. CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.68. D.hl, J. A., R.iner, A. A.FF">H., K.ungland, A., W.kayama, T. & Collas, P. A.FF">H.stone A.">A.FF">H. lysine 27 methylation asymmetry on developmental.y-regulated promoters distinguish the first two lineages in mouse preimplantation embryos. PL.S./font> ONA.FF">F.A.A.FF">F.">E.5, e9150 (2010).PubM.d.PubM.d Central.A.ticle.CA.font style="background-color:#0000CC">S./font>. A.FF">G.ogle S./font>cholar.69. A.FF">H.wkins, R. D. et al. D.stinct epigenomic landscapes of pluripotent and lineage-committed human cells. Cell S./font>tem Cell 6, 479–491 (2010).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.70. Z.u, J. et al./font>. A.FF">G.nome-wide chromatin state transitions associated with developmental.and environmental.cues. Cell 152, 642–654 (2013).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.71. W.n, B., W., A.FF">H., S./font>hinkai, Y., Irizarry, R. A. & A.FF">F.inberg, A. P. L.rge histone A.">A.FF">H. lysine 9 dimethylated chromatin blocks distinguish differentiated from embryonic stem cells. NatA.FF">G.net. 41, 246–250 (2009).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.72. T.wbin, B. D. et al. S./font>tep-wise methylation of histone A.">A.FF">H.K. positions heterochromatin at the nuclear periphery. Cell 150, 934–947 (2012).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.73. Nicetto, D. et al. A.">A.FF">H.K.me3-heterochromatin loss at protein-coding genes enables developmental.lineage specification. S./font>cience 363, 294–297 (2019).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.74. Pan, A.FF">G. et al. W.ole-genome anal.sis of histone A.">A.FF">H. lysine 4 and lysine 27 methylation in human embryonic stem cells. Cell S./font>tem Cell 1, 299–312 (2007).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.75. Z.ang, B. et al. W.despread enhancer dememorization and promoter priming during parental.to-zygotic transition. M.l. Cell 72, 673–686 (2018).PubM.d.A.ticle.CA.font style="background-color:#0000CC">S./font>. A.FF">G.ogle S./font>cholar.76. Z.eng, A.FF">H. et al. R.setting epigenetic memory by reprogramming of histone modifications in mammal.. M.l. Cell 63, 1066–1079 (2016).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.77. Z.ang, B. et al. A.lelic reprogramming of the histone modification A.">A.FF">H.K.me3 in early mammal.an development. Nature 537, 553–557 (2016).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.78. W., J. et al./font>. Chromatin anal.sis in human early development reveal. epigenetic transition during Z.font style="background-color:#FFA.FF">G.. Nature 557, 256–260 (2018).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.79. Cal., A.FF">F.A.A.FF">F.">E. & W.socka, J. M.dification of enhancer chromatin: what, how, and why? M.l. Cell 49, 825–837 (2013).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.80. W.yte, W. A. et al. A.FF">F.A.A.FF">F.">E.hancer decommissioning by L.font style="background-color:#0000CC">S./font>D. during embryonic stem cell differentiation. Nature 482, 221–225 (2012).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.81. Cui, K. et al. Chromatin signatures in multipotent human hematopoietic stem cells indicate the fate of bival.nt genes during differentiation. Cell S./font>tem Cell 4, 80–93 (2009).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.82. L.ndeman, L. C. et al./font>. Chromatin states of developmental.y-regulated genes reveal.d by D.A.and histone methylation patterns in zebrafish embryos. Int. J. D.v. B.ol. 54, 803–813 (2010).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.83. B.rd, K. N. & S./font>hearn, A. A.font style="background-color:#0000CC">S./font>A.FF">H., a D.osophila trithorax group protein, is required for methylation of lysine 4 residues on histone A.">A.FF">H.. Proc. Natl A.ad. S./font>ci. US./font>A.100, 11535–11540 (2003).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.84. Ingham, P. W. & W.ittle, A.FF">R. T.ithorax: a new homoeotic mutation of D.osophila melanogaster causing transformations of abdominal.and thoracic imaginal.segments. M.l. A.FF">G.n. A.FF">G.net. 179, 607–614 (1980).A.ticle. A.FF">G.ogle S./font>cholar.85. S./font>lifer, A.FF">F.A.A.FF">F.">E. A.FF">H. A.mutant stock of D.osophila with extra sex-combs. J. A.FF">F.A.A.FF">F.">E.p. Z.ol. 90, 31–40 (1942).A.ticle. A.FF">G.ogle S./font>cholar.86. L.wis, A.FF">F.A.A.FF">F.">E. B. A.gene complex controlling segmentation in D.osophila. Nature 276, 565–570 (1978).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.87. S./font>truhl, A.FF">G. A.gene product required for correct initiation of segmental.determination in D.osophila. Nature 293, 36–41 (1981).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.88. Jurgens, A.FF">G., W.eschaus, A.FF">F.A.A.FF">F.">E., Nusslein-V.lhard, C. & K.uding, A.FF">H. M.tations affecting the pattern of the larval.cuticle in D.osophila melanogaster: II. Z.gotic loci on the third chromosome. W.lehm R.ux A.ch. D.v. B.ol. 193, 283–295 (1984).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.89. Nusslein-V.lhard, C., W.eschaus, A.FF">F.A.A.FF">F.">E. & K.uding, A.FF">H. M.tations affecting the pattern of the larval.cuticle in D.osophila melanogaster: I. Z.gotic loci on the second chromosome. W.lehm R.ux A.ch. D.v. B.ol. 193, 267–282 (1984).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.90. W.eschaus, A.FF">F.A.A.FF">F.">E., Nusslein-V.lhard, C. & Jurgens, A.FF">G. M.tations affecting the pattern of the larval.cuticle in D.osophila melanogaster: III. Z.gotic loci on the X.chromosome and fourth chromosome. W.lehm R.ux A.ch. D.v. B.ol. 193, 296–307 (1984).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.91. T.urumi, A., D.tta, P., S./font>hang, R., Y.n, S./font>. J. & L., W. X. D.osophila K.m4 demethylases in histone A.">A.FF">H. lysine 9 demethylation and ecdysteroid signal.ng. S./font>ci. R.p. 3, 2894 (2013).PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.92. D. S./font>tefano, A.FF">L., Ji, J. Y., M.on, N. S./font>., A.FF">H.rr, A. & D.son, N. M.tation of D.osophila L.d1 disrupts A.">A.FF">H.-K. methylation, resulting in tissue-specific defects during development. Curr. B.ol. 17, 808–812 (2007).PubM.d.PubM.d Central.A.ticle.CA.font style="background-color:#0000CC">S./font>. A.FF">G.ogle S./font>cholar.93. S./font>ankar, A. et al. M.ternal.expression of the histone demethylase K.m4a is crucial.for pre-implantation development. D.velopment 144, 3264–3277 (2017).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.94. A.celin, K. et al. M.ternal.L.font style="background-color:#0000CC">S./font>D./K.font style="background-color:#A1DAEE">D.1A.is an essential.regulator of chromatin and transcription landscapes during zygotic genome activation. eL.fe 5, e08851 (2016).PubM.d.PubM.d Central.A.ticle.CA.font style="background-color:#0000CC">S./font>. A.FF">G.ogle S./font>cholar.95. W.ng, J. et al./font>. Opposing L.font style="background-color:#0000CC">S./font>D. complexes function in developmental.gene activation and repression programmes. Nature 446, 882–887 (2007).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.96. T.chiersch, B. et al. T.e protein encoded by the D.osophila position-effect variegation suppressor gene S./font>u(var)3-9 combines domains of antagonistic regulators of homeotic gene complexes. A.FF">F.A.A.FF">F.">E.B. J. 13, 3822–3831 (1994).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.97. R.uter, A.FF">G., D.rn, R., W.stmann, A.FF">G., A.FF">F.iede, B. & R.uh, A.FF">G. T.ird chromosome suppressor of position-effect variegation loci in D.osophila melanogaster. M.l. A.FF">G.n. A.FF">G.net. 202, 481–487 (1986).CA.font style="background-color:#0000CC">S./font>.A.ticle. A.FF">G.ogle S./font>cholar.98. A.dreu-V.eyra, C. V. et al. M.L. is required in oocytes for bulk histone 3 lysine 4 trimethylation and transcriptional.silencing. PL.S./font> B.ol. 8, e1000453 (2010).PubM.d.PubM.d Central.A.ticle.CA.font style="background-color:#0000CC">S./font>. A.FF">G.ogle S./font>cholar.99. D.dge, J. A.FF">F.A.A.FF">F.">E., K.ng, Y. K., B.ppu, A.FF">H., L.i, A.FF">H. & L., A.FF">F.A.A.FF">F.">E. A.FF">H.stone A.">A.FF">H.-K. methyltransferase A.FF">F.A.A.FF">F.">E.A.FF">F.A.A.FF">F.">E. is essential.for early development. M.l. Cell. B.ol. 24, 2478–2486 (2004).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.100. T.rres-Padilla, M. A.FF">F.A.A.FF">F.">E., A.FF">Parfitt, D. A.FF">F.A.A.FF">F.">E., K.uzarides, T. & Z.rnicka-A.FF">G.etz, M. A.FF">H.stone arginine methylation regulates pluripotency in the early mouse embryo. Nature 445, 214–218 (2007). S./font>eminal.study showing that different amounts of A.g methylation within four-cell blastomeres can account for their different cell fates and potencies during early development. CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.101. A.FF">Y.dav, N. et al. S./font>pecific protein methylation defects and gene expression perturbations in coactivator-associated arginine methyltransferase 1-deficient mice. Proc. Natl A.ad. S./font>ci. US./font>A.100, 6464–6468 (2003).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.102. T.e, W. W. et al. Prmt5 is essential.for early mouse development and acts in the cytoplasm to maintain A.FF">F.A.A.FF">F.">E. cell pluripotency. A.FF">G.nes D.v. 24, 2772–2777 (2010).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.103. Pawlak, M. R., S./font>cherer, C. A., Chen, J., R.shon, M. J. & R.ley, A.FF">H. A.FF">F.A.A.FF">F.">E. A.ginine N-methyltransferase 1 is required for early postimplantation mouse development, but cells deficient in the enzyme are viable. M.l. Cell. B.ol. 20, 4859–4869 (2000).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.104. A.FF">H.ss, A.FF">J. L., Y., B. D., L., B., A.FF">H.nson, R. & K.rsmeyer, S./font>. J. D.fects in yolk sac hematopoiesis in M.l-null embryos. B.ood 90, 1799–1806 (1997).CA.font style="background-color:#0000CC">S./font>.PubM.d. A.FF">G.ogle S./font>cholar.105. Jude, C. D. et al. Unique and independent roles for M.L.in adult hematopoietic stem cells and progenitors. Cell S./font>tem Cell 1, 324–337 (2007).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.106. M.M.hon, K. A. et al. M.l has a critical.role in fetal.and adult hematopoietic stem cell self-renewal. Cell S./font>tem Cell 1, 338–345 (2007).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.107. A.FF">F.A.A.FF">F.">E.nst, P. et al. D.finitive hematopoiesis requires the mixed-lineage leukemia gene. D.v. Cell 6, 437–443 (2004).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.108. S./font>al.que, S./font>., K.m, J., A.FF">R.oke, A.FF">H. M. & Orkin, S./font>. A.FF">H. A.FF">F.A.A.FF">F.">E.igenetic regulation of hematopoietic differentiation by A.FF">G.i-1 and A.FF">G.i-1b is mediated by the cofactors CoR.font style="background-color:#A.FF">F.A.A.FF">F.">E.T.and L.font style="background-color:#0000CC">S./font>D.. M.l. Cell 27, 562–572 (2007). A.D.font style="background-color:#FFAAFF">A.E">Identification of a role and mechanism for L.font style="background-color:#0000CC">S./font>D. in regulating haematopoietic differentiation. CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.109. T.ambyrajah, R. et al. A.FF">G.font style="background-color:#FFA.FF">F.1 proteins orchestrate the emergence of haematopoietic stem cells through recruitment of L.font style="background-color:#0000CC">S./font>D.. Nat. Cell B.ol. 18, 21–32 (2016).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.110. S./font>prussel, A. et al. L.sine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential.for terminal.differentiation. B.E">L.ukemia 26, 2039–2051 (2012).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.111. K.renyi, M. A. et al. A.FF">H.stone demethylase L.d1 represses hematopoietic stem and progenitor cell signatures during blood cell maturation. eL.fe 2, e00633 (2013).PubM.d.PubM.d Central.A.ticle.CA.font style="background-color:#0000CC">S./font>. A.FF">G.ogle S./font>cholar.112. Ugarte, A.FF">F. et al. Progressive chromatin condensation and A.">A.FF">H.K. methylation regulate the differentiation of embryonic and hematopoietic stem cells. S./font>tem Cell R.p. 5, 728–740 (2015).CA.font style="background-color:#0000CC">S./font>.A.ticle. A.FF">G.ogle S./font>cholar.113. van der L.gt, N. M. et al. Posterior transformation, neurological.abnormal.ties, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene. A.FF">G.nes D.v. 8, 757–769 (1994).PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.114. Ikeda, K. et al. M.intenance of the functional.integrity of mouse hematopoiesis by A.FF">F.A.A.FF">F.">E.D.and promotion of leukemogenesis by A.FF">F.A.A.FF">F.">E.D.haploinsufficiency. S./font>ci. R.p. 6, 29454 (2016).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.115. Oettinger, M. A., S./font>chatz, D. A.FF">G., A.FF">G.rka, C. & B.ltimore, D. R.font style="background-color:#FFAAFF">A.font style="background-color:#FFA.FF">G.1 and R.font style="background-color:#FFAAFF">A.font style="background-color:#FFA.FF">G.2, adjacent genes that synergistical.y activate V.D.J recombination. S./font>cience 248, 1517–1523 (1990).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.116. A., S./font>. et al. D.vergent requirements for A.FF">F.A.A.FF">F.">E.A.FF">H. in heart development versus regeneration. Circ. R.s. 121, 106–112 (2017).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.117. A., S./font>. et al. A.FF">F.A.A.FF">F.">E.D.orchestration of heart maturation through interaction with A.FF">H.A.s is A.">A.FF">H.K.7me3-independent. eL.fe 6, e24570 (2017).PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.118. A.erberg, A. A., A.FF">H.nner, A., S./font>tewart, S./font>. & S./font>tankunas, K. A.FF">H.stone demethylases A.FF">F.A.A.FF">F.">K.m6ba and A.FF">F.A.A.FF">F.">K.m6bb redundantly promote cardiomyocyte proliferation during zebrafish heart ventricle maturation. D.v. B.ol. 426, 84–96 (2017).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.119. L.n, A.FF">F. et al. A.histone A.">A.FF">H. lysine 27 demethylase regulates animal.posterior development. Nature 449, 689–694 (2007).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.120. W.jayatunge, R. et al. T.e histone demethylase A.FF">F.A.A.FF">F.">K.m6b regulates a mature gene expression program in differentiating cerebellar granule neurons. M.l. Cell. Neurosci. 87, 4–17 (2018).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.121. Park, D. A.FF">H. et al. A.tivation of neuronal.gene expression by the JM.D. demethylase is required for postnatal.and adult brain neurogenesis. Cell R.p. 8, 1290–1299 (2014).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.122. A.FF">G.u, Y. et al. A.C8EA.FF">F.>Protein arginine methyltransferase PR.font style="background-color:#A1DAEE">M.1 is essential.for pal.togenesis. J. D.nt. R.s. 97, 1510–1518 (2018).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.123. Iwase, S./font>. et al. A.mouse model of X.linked intellectual.disability associated with impaired removal.of histone methylation. Cell R.p. 14, 1000–1009 (2016).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.124. S./font>candaglia, M. et al. L.ss of K.m5c causes spurious transcription and prevents the fine-tuning of activity-regulated enhancers in neurons. Cell R.p. 21, 47–59 (2017).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.125. L.m, D. A. et al. Chromatin remodelling factor M.l1 is essential.for neurogenesis from postnatal.neural.stem cells. Nature 458, 529–533 (2009).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.126. B.zzi, M. et al. R.gulation of constitutive and al.ernative splicing by PR.font style="background-color:#A1DAEE">M.5 reveal. a role for M.m4 pre-mR.A.in sensing defects in the spliceosomal.machinery. A.FF">G.nes D.v. 27, 1903–1916 (2013).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.127. A.FF">H.shimoto, M. et al. S./font>evere hypomyelination and developmental.defects are caused in mice lacking protein arginine methyltransferase 1 (PR.font style="background-color:#A1DAEE">M.1) in the central.nervous system. J. B.ol. Chem. 291, 2237–2245 (2016).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.128. Chittka, A., Nitarska, J., A.FF">G.azini, U. & R.chardson, W. D. T.anscription factor positive regulatory domain 4 (PR.font style="background-color:#A1DAEE">D.4) recruits protein arginine methyltransferase 5 (PR.font style="background-color:#A1DAEE">M.5) to mediate histone arginine methylation and control neural.stem cell proliferation and differentiation. J. B.ol. Chem. 287, 42995–43006 (2012).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.129. D.ar, S./font>. S./font>. et al. M.L. is required to maintain broad A.">A.FF">H.K.me3 peaks and super-enhancers at tumor suppressor genes. M.l. Cell 70, 825–841 (2018).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.130. Inagaki, T. et al. Obesity and metabolic syndrome in histone demethylase JA.FF">H.M.a-deficient mice. A.FF">G.nes Cells 14, 991–1001 (2009).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.131. T.teishi, K., Okada, Y., K.llin, A.FF">F.A.A.FF">F.">E. M. & Z.ang, Y. R.le of Jhdm2a in regulating metabolic gene expression and obesity resistance. Nature 458, 757–761 (2009).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.132. A.FF">K.roki, S./font>. et al. A.FF">F.A.A.FF">F.">E.igenetic regulation of mouse sex determination by the histone demethylase Jmjd1a. S./font>cience 341, 1106–1109 (2013).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.133. Okada, Y., S./font>cott, A.FF">G., R.y, M. K., M.shina, Y. & Z.ang, A.FF">F.A.A.FF">F.">Y. A.FF">H.stone demethylase JA.FF">H.M.A.is critical.for T.p1 and Prm1 transcription and spermatogenesis. Nature 450, 119–123 (2007).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.134. B.swell, R. A.FF">F.A.A.FF">F.">E. & M.howal., A. P. tudor, a gene required for assembly of the germ plasm in D.osophila melanogaster. Cell 43, 97–104 (1985).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.135. Capra, J. A. A.FF">F.A.A.FF">F.">E.trapolating histone marks across developmental.stages, tissues, and species: an enhancer prediction case study. B.C A.FF">G.nomics 16, 104 (2015).PubM.d.PubM.d Central.A.ticle.CA.font style="background-color:#0000CC">S./font>. A.FF">G.ogle S./font>cholar.136. Plath, K. et al. R.le of histone A.">A.FF">H. lysine 27 methylation in X.inactivation. S./font>cience 300, 131–135 (2003). D.monstration of the mechanism of X.chromosome inactivation via recruitment of PR.2 by X.st R.A. CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.137. Inoue, A., Jiang, L., L., A.FF">F. & Z.ang, Y. A.FF">G.nomic imprinting of X.st by maternal.A.">A.FF">H.K.7me3. A.FF">G.nes D.v. 31, 1927–1932 (2017).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.138. W.ng, J. et al./font>. Imprinted X.inactivation maintained by a mouse Polycomb group gene. Nat. A.FF">G.net. 28, 371–375 (2001).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle.PubM.d Central. A.FF">G.ogle S./font>cholar.139. Inoue, A., Chen, Z., Y.n, Q. & Z.ang, Y. M.ternal.A.FF">F.A.A.FF">F.">E.d knockout causes loss of A.">A.FF">H.K.7me3 imprinting and random X.inactivation in the extraembryonic cells. A.FF">G.nes D.v. 32, 1525–1536 (2018).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.140. L.ndroth, A. M. et al. A.tagonism between D.A.and A.">A.FF">H.K.7 methylation at the imprinted R.sgrf1 locus. PL.S./font> A.FF">G.net. 4, e1000145 (2008).PubM.d.PubM.d Central.A.ticle.CA.font style="background-color:#0000CC">S./font>. A.FF">G.ogle S./font>cholar.141. Inoue, A., Jiang, L., L., A.FF">F., S./font>uzuki, T. & Z.ang, Y. M.ternal.A.">A.FF">H.K.7me3 controls D.A.methylation-independent imprinting. Nature 547, 419–424 (2017). D.monstration of a histone-based mechanism of imprinting by A.">A.FF">H.K.7 methylation. CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.142. K.zmin, A. et al. T.e PcA.FF">G.gene S./font>fmbt2 is paternal.y expressed in extraembryonic tissues. A.FF">G.ne A.FF">F.A.A.FF">F.">E.pr. Patterns 8, 107–116 (2008).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.143. M.ri, K. et al. T.e imprinted polycomb group gene S./font>fmbt2 is required for trophoblast maintenance and placenta development. D.velopment 140, 4480–4489 (2013).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.144. A.FF">H.rding, K., W.deen, C., M.A.FF">G.nnis, W. & L.vine, M. S./font>patial.y regulated expression of homeotic genes in D.osophila. S./font>cience 229, 1236–1242 (1985).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.145. K.ndo, T. & D.boule, D. B.eaking colinearity in the mouse A.FF">H.xD.complex. Cell 97, 407–417 (1999).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.146. S./font>oshnikova, N. & D.boule, D. A.FF">F.A.A.FF">F.">E.igenetic temporal.control of mouse A.FF">H.x genes in vivo. S./font>cience 324, 1320–1323 (2009).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.147. Ingham, P. W. D.fferential.expression of B.thorax complex genes in the absence of the A.FF">F.A.A.FF">F.">E.tra sex combs and T.ithorax genes. Nature 306, 591–593 (1983). A.FF">F.rst demonstration that T.ithorax and Polycomb genes have opposing effects on A.FF">H.x gene expression. CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.148. S./font>imon, J., A.FF">F.A.A.FF">F.">Chiang, A. & B.nder, W. T.n different Polycomb group genes are required for spatial.control of the abdA.and A.dB.homeotic products. D.velopment 114, 493–505 (1992).CA.font style="background-color:#0000CC">S./font>.PubM.d. A.FF">G.ogle S./font>cholar.149. S./font>truhl, A.FF">G. & A.am, M. A.tered distributions of Ultrabithorax transcripts in extra sex combs mutant embryos of D.osophila. A.FF">F.A.A.FF">F.">E.B. J. 4, 3259–3264 (1985).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.150. K.ymenko, T. & M.ller, J. T.e histone methyltransferases T.ithorax and A.h1 prevent transcriptional.silencing by Polycomb group proteins. A.FF">F.A.A.FF">F.">E.B. R.p. 5, 373–377 (2004).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.151. Y.gi, A.FF">H. et al. A.FF">G.owth disturbance in fetal.liver hematopoiesis of M.l-mutant mice. B.ood 92, 108–117 (1998).CA.font style="background-color:#0000CC">S./font>.PubM.d. A.FF">G.ogle S./font>cholar.152. Y., B. D., A.FF">H.nson, R. D., A.FF">H.ss, A.FF">J. L., A.FF">H.rning, S./font>. A.FF">F.A.A.FF">F.">E. & K.rsmeyer, S./font>. J. M.L. a mammal.an trithorax-group gene, functions as a transcriptional.maintenance factor in morphogenesis. Proc. Natl A.ad. S./font>ci. US./font>A.95, 10632–10636 (1998).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.153. Y., B. D., A.FF">H.ss, A.FF">J. L., A.FF">H.rning, S./font>. A.FF">F.A.A.FF">F.">E., B.own, A.FF">G. A.K.rsmeyer, S./font>. J. A.tered A.FF">H.x expression and segmental.identity in M.l-mutant mice. Nature 378, 505–508 (1995). Initial.link between M.L. and A.FF">H.X.gene expression during mammal.an embryogenesis. CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.154. B.een, T. R. & A.FF">H.rte, P. J. M.lecular characterization of the trithorax gene, a positive regulator of homeotic gene expression in D.osophila. M.ch. D.v. 35, 113–127 (1991).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.155. A.FF">F.ster, A.FF">C. T. et al. L.sine-specific demethylase 1 regulates the embryonic transcriptome and CoR.font style="background-color:#A.FF">F.A.A.FF">F.">E.T.stability. M.l. Cell. B.ol. 30, 4851–4863 (2010).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.156. A.g, S./font>. Y. et al. K.font style="background-color:#A1DAEE">M.2D.regulates specific programs in heart development via histone A.">A.FF">H. lysine 4 di-methylation. D.velopment 143, 810–821 (2016).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.157. B.edau, A. S./font>. et al. T.e A.">A.FF">H.K. methyltransferase S./font>etd1a is first required at the epiblast stage, whereas A.FF">F.A.A.FF">F.">S./font>etd1b becomes essential.after gastrulation. D.velopment 141, 1022–1035 (2014).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.158. A.FF">G.aser, S./font>. et al. M.ltiple epigenetic maintenance factors implicated by the loss of M.l2 in mouse development. D.velopment 133, 1423–1432 (2006).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.159. W., M. et al. M.lecular regulation of A.">A.FF">H.K. trimethylation by W.r82, a component of human S./font>et1/COM.A.font style="background-color:#0000CC">S./font>S./font>. M.l. Cell. B.ol. 28, 7337–7344 (2008).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.160. M.lne, T. A. et al. M.L.targets S./font>A.FF">F.A.A.FF">F.">E. domain methyltransferase activity to A.FF">H.x gene promoters. M.l. Cell 10, 1107–1117 (2002).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.161. A.FF">H., D. et al. T.e M.L./M.L. branches of the COM.A.font style="background-color:#0000CC">S./font>S./font> family function as major histone A.">A.FF">H.K. monomethylases at enhancers. M.l. Cell. B.ol. 33, 4745–4754 (2013).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.162. O’Carroll, D. et al. T.e polycomb-group gene A.FF">F.A.A.FF">F.">E.h2 is required for early mouse development. M.l. Cell. B.ol. 21, 4330–4336 (2001).PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.163. A.FF">H.ang, X. J. et al./font>. A.FF">F.A.A.FF">F.">E.A.FF">H. is essential.for development of mouse preimplantation embryos. R.prod. A.FF">F.rtil. D.v. 26, 1166–1175 (2014).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.164. W.ngaarden, L. A., D.lgado-Olguin, P., S./font>u, I. A.FF">H., B.uneau, B. A.FF">G. & A.FF">H.pyan, S./font>. A.FF">F.A.A.FF">F.">E.h2 regulates anteroposterior axis specification and proximodistal.axis elongation in the developing limb. D.velopment 138, 3759–3767 (2011).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.165. S./font>chwarz, D. et al. A.FF">F.A.A.FF">F.">E.h2 is required for neural.crest-derived cartilage and bone formation. D.velopment 141, 867–877 (2014).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle.PubM.d Central. A.FF">G.ogle S./font>cholar.166. A.FF">F.ust, C., L.wson, K. A., S./font>chork, N. J., T.iel, B. & M.gnuson, T. T.e Polycomb-group gene eed is required for normal.morphogenetic movements during gastrulation in the mouse embryo. D.velopment 125, 4495–4506 (1998).CA.font style="background-color:#0000CC">S./font>.PubM.d. A.FF">G.ogle S./font>cholar.167. A.FF">F.ust, C., S./font>chumacher, A., A.FF">H.ldener, B. & M.gnuson, T. T.e eed mutation disrupts anterior mesoderm production in mice. D.velopment 121, 273–285 (1995).CA.font style="background-color:#0000CC">S./font>.PubM.d. A.FF">G.ogle S./font>cholar.168. Pasini, D., B.acken, A. P., Jensen, M. R., L.zzerini D.nchi, A.FF">F.A.A.FF">F.">E. & A.FF">H.lin, K. S./font>uz12 is essential.for mouse development and for A.FF">F.A.A.FF">F.">E.A.FF">H. histone methyltransferase activity. A.FF">F.A.A.FF">F.">E.B. J. 23, 4061–4071 (2004).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.169. van der L.gt, N. M., A.kema, M., B.rns, A. & D.schamps, J. T.e Polycomb-group homolog B.i-1 is a regulator of murine A.FF">H.x gene expression. M.ch. D.v. 58, 153–164 (1996).PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.170. A.ger, K. et al. UT.font style="background-color:#FFAAFF">X.and JM.D. are histone A.">A.FF">H.K.7 demethylases involved in A.FF">H.X.gene regulation and development. Nature 449, 731–734 (2007).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.171. S./font>hpargel, K. B., S./font>engoku, T., Y.koyama, S./font>. & M.gnuson, T. UT.font style="background-color:#FFAAFF">X./font> and UT.font style="background-color:#FFAAFF">Y.demonstrate histone demethylase-independent function in mouse embryonic development. PL.S./font> A.FF">G.net. 8, e1002964 (2012). T.is paper shows a catal.tical.y independent role of K.font style="background-color:#A1DAEE">D.6A.in recruiting chromatin regulators that can be substituted for by the catal.tical.y inactive K.font style="background-color:#A1DAEE">D.6C. CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.172. A.FF">H.ng, S./font>. et al. A.D.font style="background-color:#FFAAFF">A.E">Identification of JmjC domain-containing UT.font style="background-color:#FFAAFF">X.and JM.D. as histone A.">A.FF">H. lysine 27 demethylases. Proc. Natl A.ad. S./font>ci. US./font>A.104, 18439–18444 (2007).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.173. Naruse, C. et al. New insights into the role of Jmjd3 and Utx in axial.skeletal.formation in mice. A.FF">F.S./font>A.FF">F.A.A.FF">F.">E. J. 31, 2252–2266 (2017).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.174. D.nissov, S./font>. et al. M.l2 is required for A.">A.FF">H.K. trimethylation on bival.nt promoters in embryonic stem cells, whereas M.l1 is redundant. D.velopment 141, 526–537 (2014).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.175. Z.ang, A.FF">H. et al. M.L. inhibition reprograms epiblast stem cells to naive pluripotency. Cell S./font>tem Cell 18, 481–494 (2016).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.176. L.bitz, S./font>., A.FF">G.aser, S./font>., S./font>chaft, J., S./font>tewart, A. A.FF">F. & A.astassiadis, K. Increased apoptosis and skewed differentiation in mouse embryonic stem cells lacking the histone methyltransferase M.l2. M.l. B.ol. Cell 18, 2356–2366 (2007).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.177. A.FF">G.aser, S./font>. et al. T.e histone 3 lysine 4 methyltransferase, M.l2, is only required briefly in development and spermatogenesis. A.FF">F.A.A.FF">F.">E.igenetics Chromatin 2, 5 (2009).PubM.d.PubM.d Central.A.ticle.CA.font style="background-color:#0000CC">S./font>. A.FF">G.ogle S./font>cholar.178. S./font>ze, C. C. et al. A.FF">H.stone A.">A.FF">H.K. methylation-dependent and -independent functions of S./font>et1A.COM.A.font style="background-color:#0000CC">S./font>S./font> in embryonic stem cell self-renewal.and differentiation. A.FF">G.nes D.v. 31, 1732–1737 (2017).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.179. T.chibana, M. et al. A.FF">G.a histone methyltransferase plays a dominant role in euchromatic histone A.">A.FF">H. lysine 9 methylation and is essential.for early embryogenesis. A.FF">G.nes D.v. 16, 1779–1791 (2002).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.180. Obier, N. et al. Polycomb protein A.FF">F.A.A.FF">F.">E.D.is required for silencing of pluripotency genes upon A.FF">F.A.A.FF">F.">E.C differentiation. S./font>tem Cell R.v. 11, 50–61 (2015).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.181. Jiang, W., W.ng, J. & Z.ang, A.FF">F.A.A.FF">F.">Y. A.FF">H.stone A.">A.FF">H.K.7me3 demethylases K.font style="background-color:#A1DAEE">D.6A.and K.font style="background-color:#A1DAEE">D.6B.modulate definitive endoderm differentiation from human A.FF">F.A.A.FF">F.">E.Cs by regulating W.T.signal.ng pathway. Cell R.s. 23, 122–130 (2013).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.182. L.e, S./font>., L.e, J. W. & L.e, S./font>. K. UT.font style="background-color:#FFAAFF">X. a histone A.">A.FF">H.-lysine 27 demethylase, acts as a critical.switch to activate the cardiac developmental.program. D.v. Cell 22, 25–37 (2012).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.183. A.amo, A. et al. L.font style="background-color:#0000CC">S./font>D. regulates the bal.nce between self-renewal.and differentiation in human embryonic stem cells. Nat. Cell B.ol. 13, 652–659 (2011).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.184. L.h, A.FF">F.A.A.FF">F.">Y. A.FF">H., Z.ang, W., Chen, X., A.FF">G.orge, J. & Ng, A.FF">H. A.FF">H. Jmjd1a and Jmjd2c histone A.">A.FF">H. L.s 9 demethylases regulate self-renewal.in embryonic stem cells. A.FF">G.nes D.v. 21, 2545–2557 (2007).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.185. W., Q. et al./font>. CA.M. is required in embryonic stem cells to maintain pluripotency and resist differentiation. S./font>tem Cells 27, 2637–2645 (2009).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.186. X., Z. et al. M.croR.A.181 regulates CA.M. and histone arginine methylation to promote differentiation of human embryonic stem cells. PL.S./font> ONA.FF">F.A.A.FF">F.">E.8, e53146 (2013).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.187. Cao, K. et al. S./font>A.FF">F.A.A.FF">F.">E.1A.COM.A.font style="background-color:#0000CC">S./font>S./font> and shadow enhancers in the regulation of homeotic gene expression. A.FF">G.nes D.v. 31, 787–801 (2017).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.188. T.maz, R. A. et al. Jmjd2c facilitates the assembly of essential.enhancer-protein complexes at the onset of embryonic stem cell differentiation. D.velopment 144, 567–579 (2017).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.189. W.n, X. et al. M.l2 controls cardiac lineage differentiation of mouse embryonic stem cells by promoting A.">A.FF">H.K.me3 deposition at cardiac-specific genes. S./font>tem Cell R.v. 10, 643–652 (2014).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.190. L.e, A.FF">F.A.A.FF">F.">Y. A.FF">H. et al. A.C8EA.FF">F.>Protein arginine methyltransferase 6 regulates embryonic stem cell identity. S./font>tem Cells D.v. 21, 2613–2622 (2012).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.191. M., D. K., A.FF">F.A.A.FF">F.">Chiang, C. A.FF">H., Ponnusamy, K., M.ng, A.FF">G. L. & S./font>ong, A.FF">H. A.FF">G.a and Jhdm2a regulate embryonic stem cell fusion-induced reprogramming of adult neural.stem cells. S./font>tem Cells 26, 2131–2141 (2008).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.192. A.g, Y. S./font>. et al. W.r5 mediates self-renewal.and reprogramming via the embryonic stem cell core transcriptional.network. Cell 145, 183–197 (2011).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.193. Jones, W. D. et al. D. novo mutations in M.L.cause W.edemann–S./font>teiner syndrome. A.. J. A.FF">H.m. A.FF">G.net. 91, 358–364 (2012).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.194. M.yer, A.FF">F.A.A.FF">F.">E. et al. M.tations in the histone methyltransferase gene K.font style="background-color:#A1DAEE">M.2B.cause complex early-onset dystonia. Nat. A.FF">G.net. 49, 223–237 (2017).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.195. K.eefstra, T. et al. D.sruption of an A.FF">F.A.A.FF">F.">E.M.1-associated chromatin-modification module causes intellectual.disability. A.. J. A.FF">H.m. A.FF">G.net. 91, 73–82 (2012).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.196. D. R.beis, S./font>. et al. S./font>ynaptic, transcriptional.and chromatin genes disrupted in autism. Nature 515, 209–215 (2014).PubM.d.PubM.d Central.A.ticle.CA.font style="background-color:#0000CC">S./font>. A.FF">G.ogle S./font>cholar.197. A.FF">H.nnibal. M. C. et al. S./font>pectrum of M.L. (A.R. mutations in 110 cases of K.buki syndrome. A.. J. M.d. A.FF">G.net. A.155A. 1511–1516 (2011).PubM.d.A.ticle.CA.font style="background-color:#0000CC">S./font>. A.FF">G.ogle S./font>cholar.198. Ng, S./font>. B. et al. A.FF">F.A.A.FF">F.">E.ome sequencing identifies M.L. mutations as a cause of K.buki syndrome. Nat. A.FF">G.net. 42, 790–793 (2010).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.199. A.FF">H.raide, T. et al. D. novo variants in S./font>A.FF">F.A.A.FF">F.">E.D.B.are associated with intellectual.disability, epilepsy and autism. A.FF">H.m. A.FF">G.net. 137, 95–104 (2018).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.200. A.idi, A.FF">F. A.FF">F.A.A.FF">F.">E. et al. M.tations in JA.ID.C are associated with X.linked mental.retardation, short stature and hyperreflexia. J. M.d. A.FF">G.net. 45, 787–793 (2008).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.201. A.FF">G.ncal.es, T. A.FF">F. et al. K.font style="background-color:#A1DAEE">D.5C mutational.screening among mal.s with intellectual.disability suggestive of X.L.nked inheritance and review of the literature. A.FF">F.A.A.FF">F.">E.r. J. M.d. A.FF">G.net. 57, 138–144 (2014).PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.202. Jensen, L. R. et al./font>. M.tations in the JA.ID.C gene, which is involved in transcriptional.regulation and chromatin remodeling, cause X.linked mental.retardation. A.. J. A.FF">H.m. A.FF">G.net. 76, 227–236 (2005).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.203. Chong, J. X. et al./font>. A.FF">G.ne discovery for M.ndelian conditions via social.networking: de novo variants in K.font style="background-color:#A1DAEE">D.1A.cause developmental.delay and distinctive facial.features. A.FF">G.net. M.d. 18, 788–795 (2016).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.204. T.novic, S./font>., B.rkovich, J., S./font>herr, A.FF">F.A.A.FF">F.">E. A.FF">H. & S./font>lavotinek, A. M. D. novo A.K.D.1 and K.font style="background-color:#A1DAEE">D.1A.gene mutations in a mal. with features of K.font style="background-color:#FFAAFF">B.font style="background-color:#FFA.FF">G.syndrome and K.buki syndrome. A.. J. M.d. A.FF">G.net. A.164A. 1744–1749 (2014).PubM.d.A.ticle.CA.font style="background-color:#0000CC">S./font>. A.FF">G.ogle S./font>cholar.205. K.m, A.FF">H. A.FF">G. et al. T.anslocations disrupting PA.FF">H.font style="background-color:#FFA.FF">F.1A.in the Potocki-S./font>haffer-syndrome region are associated with intellectual.disability and craniofacial.anomal.es. A.. J. A.FF">H.m. A.FF">G.net. 91, 56–72 (2012).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.206. A.FF">H.rton, J. R. et al. A.FF">F.A.A.FF">F.">E.zymatic and structural.insights for substrate specificity of a family of jumonji histone lysine demethylases. Nat. S./font>truct. M.l. B.ol. 17, 38–43 (2010).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.207. A.FF">F.ng, W., Y.nezawa, M., Y., J., Jenuwein, T. & A.FF">G.ummt, I. PA.FF">H.font style="background-color:#FFA.FF">F. activates transcription of rR.A.genes through A.">A.FF">H.K.me3 binding and A.">A.FF">H.K.me1/2 demethylation. Nat. S./font>truct. M.l. B.ol. 17, 445–450 (2010).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.208. A.idi, A.FF">F., M.ano, M., M.rray, J. & S./font>chwartz, C. A.novel mutation in the PA.FF">H.font style="background-color:#FFA.FF">F. gene is associated with X.linked mental.retardation with cleft lip/cleft pal.te. Clin. A.FF">G.net. 72, 19–22 (2007).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.209. K.ivisto, A. M. et al. S./font>creening of mutations in the PA.FF">H.font style="background-color:#FFA.FF">F. gene and identification of a novel mutation in a A.FF">F.nnish family with X.font style="background-color:#CC9900">L.font style="background-color:#A1DAEE">M. and cleft lip/cleft pal.te. Clin. A.FF">G.net. 72, 145–149 (2007).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.210. L.umonnier, A.FF">F. et al. M.tations in PA.FF">H.font style="background-color:#FFA.FF">F. are associated with X.linked mental.retardation and cleft lip/cleft pal.te. J. M.d. A.FF">G.net. 42, 780–786 (2005).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.211. K.eefstra, T. et al. D.sruption of the gene euchromatin histone methyl transferase1 (A.FF">F.A.A.FF">F.">E.-A.FF">H.T.se1) is associated with the 9q34 subtelomeric deletion syndrome. J. M.d. A.FF">G.net. 42, 299–306 (2005).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.212. Qi, A.FF">H. A.FF">H. et al. A.FF">H.stone A.">A.FF">H.K.0/A.">A.FF">H.K. demethylase PA.FF">H.font style="background-color:#FFA.FF">F. regulates zebrafish brain and craniofacial.development. Nature 466, 503–507 (2010).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.213. Iacono, A.FF">G. et al. Increased A.">A.FF">H.K. methylation and impaired expression of Protocadherins are associated with the cognitive dysfunctions of the K.eefstra syndrome. Nucleic A.ids R.s. 46, 4950–4965 (2018).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.214. A.FF">G.bson, W. T. et al. M.tations in A.FF">F.A.A.FF">F.">E.A.FF">H. cause W.aver syndrome. A.. J. A.FF">H.m. A.FF">G.net. 90, 110–118 (2012).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.215. D.uglas, J. et al./font>. NS./font>D. mutations are the major cause of S./font>otos syndrome and occur in some cases of W.aver syndrome but are rare in other overgrowth phenotypes. A.. J. A.FF">H.m. A.FF">G.net. 72, 132–143 (2003). D.scribes non-overlapping sets of point mutations or deletions in NS./font>D. that are associated with two distinct syndromes. CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.216. R.o, M. et al. S./font>pectrum of NS./font>D. mutations in S./font>otos and W.aver syndromes. J. M.d. A.FF">G.net. 40, 436–440 (2003).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.217. B.ujat, A.FF">G. et al. Paradoxical.NS./font>D. mutations in B.ckwith–W.edemann syndrome and 11p15 anomal.es in S./font>otos syndrome. A.. J. A.FF">H.m. A.FF">G.net. 74, 715–720 (2004).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.218. B.nnett, R. L., S./font>waroop, A., T.oche, C. & L.cht, J. D. T.e role of nuclear receptor-binding S./font>A.FF">F.A.A.FF">F.">E. domain family histone lysine methyltransferases in cancer. Cold S./font>pring. A.FF">A.FF">H.rb. Perspect. M.d. 7, a026708 (2017).PubM.d.PubM.d Central.A.ticle.CA.font style="background-color:#0000CC">S./font>. A.FF">G.ogle S./font>cholar.219. L.ugesen, A., A.FF">H.jfeldt, J. W. & A.FF">H.lin, A.FF">F.A.A.FF">F.">K. R.le of the polycomb repressive complex 2 (PR.2) in transcriptional.regulation and cancer. Cold S./font>pring A.FF">A.FF">H.rb. Perspect. M.d. 6, a026575 (2016).PubM.d.PubM.d Central.A.ticle.CA.font style="background-color:#0000CC">S./font>. A.FF">G.ogle S./font>cholar.220. A.FF">M.chal.k, A.FF">F.A.A.FF">F.">E. W., B.rr, M. L., B.nnister, A. J. & D.wson, M. A. T.e roles of D.A. R.A.and histone methylation in ageing and cancer. Nat. R.v. M.l. Cell B.ol. https://doi.org/10.1038/s41580-019-0143-1 (2019).221. R.hman, N. M.chanisms predisposing to childhood overgrowth and cancer. Curr. Opin. A.FF">G.net. D.v. 15, 227–233 (2005).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.222. A.awi, N. et al. D.scovery of four recessive developmental.disorders using probabilistic genotype and phenotype matching among 4,125 families. Nat. A.FF">G.net. 47, 1363–1369 (2015).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.223. A.FF">F.undes, V. et al. A.FF">H.stone lysine methylases and demethylases in the landscape of human developmental.disorders. A.. J. A.FF">H.m. A.FF">G.net. 102, 175–187 (2018).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.224. Pilotto, S./font>. et al. L.font style="background-color:#0000CC">S./font>D./K.font style="background-color:#A1DAEE">D.1A.mutations associated to a newly described form of intellectual.disability impair demethylase activity and binding to transcription factors. A.FF">H.m. M.l. A.FF">G.net. 25, 2578–2587 (2016).CA.font style="background-color:#0000CC">S./font>.PubM.d. A.FF">G.ogle S./font>cholar.225. B.ookes, A.FF">F.A.A.FF">F.">E. et al. M.tations in the intellectual.disability gene K.font style="background-color:#A1DAEE">D.5C reduce protein stability and demethylase activity. A.FF">H.m. M.l. A.FF">G.net. 24, 2861–2872 (2015).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.226. B.anc, R. S./font>., V.gel, A.FF">G., Chen, T., Crist, C. & R.chard, S./font>. PR.font style="background-color:#A1DAEE">M.7 preserves satellite cell regenerative capacity. Cell R.p. 14, 1528–1539 (2016).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.227. B.uchard, C. et al. A.FF">G.nomic location of PR.font style="background-color:#A1DAEE">M.6-dependent A.">A.FF">H.R. methylation is linked to the transcriptional.outcome of associated genes. Cell R.p. 24, 3339–3352 (2018).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.228. A.FF">G.ccione, A.FF">F.A.A.FF">F.">E. et al. M.thylation of histone A.">A.FF">H.R. by PR.font style="background-color:#A1DAEE">M.6 and A.">A.FF">H.K. by an M.L.complex are mutual.y exclusive. Nature 449, 933–937 (2007). D.scribes antagonism between M.L.methyltransferases and PR.font style="background-color:#A1DAEE">M.6 in depositing A.">A.FF">H.K. and A.">A.FF">H.R. methylation, respectively. CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.229. L.e, M. A.FF">G. et al. A.FF">F.nctional.interplay between histone demethylase and deacetylase enzymes. M.l. Cell. B.ol. 26, 6395–6402 (2006).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.230. S./font>hi, A.FF">F.A.A.FF">F.">Y. J. et al./font>. R.gulation of L.font style="background-color:#0000CC">S./font>D. histone demethylase activity by its associated factors. M.l. Cell 19, 857–864 (2005).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.231. Y.n, A.FF">F. et al. L.font style="background-color:#0000CC">S./font>D. regulates pluripotency of embryonic stem/carcinoma cells through histone deacetylase 1-mediated deacetylation of histone A.">A.FF">H. at lysine 16. M.l. Cell. B.ol. 34, 158–179 (2014).PubM.d.PubM.d Central.A.ticle.CA.font style="background-color:#0000CC">S./font>. A.FF">G.ogle S./font>cholar.232. S./font>tein, C., Notzold, R. R., R.edl, S./font>., B.uchard, C. & B.uer, U. M. T.e arginine methyltransferase PR.font style="background-color:#A1DAEE">M.6 cooperates with Polycomb proteins in regulating A.FF">H.X.font style="background-color:#FFAAFF">A.gene expression. PL.S./font> ONA.FF">F.A.A.FF">F.">E.11, e0148892 (2016).PubM.d.PubM.d Central.A.ticle.CA.font style="background-color:#0000CC">S./font>. A.FF">G.ogle S./font>cholar.233. A.FF">F.i, Q. et al./font>. S./font>A.FF">F.A.A.FF">F.">E.D.font style="background-color:#FFAAFF">B. modulates PR.2 activity at developmental.genes independently of A.">A.FF">H.K. trimethylation in mouse A.FF">F.A.A.FF">F.">E. cells. A.FF">G.nome R.s. 25, 1325–1335 (2015).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.234. Cao, K. et al. A. M.l4/COM.A.font style="background-color:#0000CC">S./font>S./font>-L.d1 epigenetic axis governs enhancer function and pluripotency transition in embryonic stem cells. S./font>ci. A.v. 4, eaap8747 (2018).PubM.d.PubM.d Central.A.ticle.CA.font style="background-color:#0000CC">S./font>. A.FF">G.ogle S./font>cholar.235. Cho, Y. W. et al. PT.P associates with M.L.- and M.L.-containing histone A.">A.FF">H. lysine 4 methyltransferase complex. J. B.ol. Chem. 282, 20395–20406 (2007).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.236. Issaeva, I. et al. K.ockdown of A.R.(M.L.) reveal. A.R.target genes and leads to al.erations in cell adhesion and growth. M.l. Cell. B.ol. 27, 1889–1903 (2007).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.237. L.e, M. A.FF">G. et al. D.methylation of A.">A.FF">H.K.7 regulates polycomb recruitment and A.FF">H.A.ubiquitination. S./font>cience 318, 447–450 (2007).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.238. W.ng, S./font>. P. et al. A.UT.font style="background-color:#FFAAFF">X.M.L.-p300 transcriptional.regulatory network coordinately shapes active enhancer landscapes for eliciting transcription. M.l. Cell 67, 308–321 (2017).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.239. M.ller, S./font>. A., M.hn, S./font>. A.FF">F.A.A.FF">F.">E. & W.inmann, A. S./font>. Jmjd3 and UT.font style="background-color:#FFAAFF">X.play a demethylase-independent role in chromatin remodeling to regulate T.box family member-dependent gene expression. M.l. Cell 40, 594–605 (2010).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.240. Ooi, S./font>. K. et al. D.M.3L.connects unmethylated lysine 4 of histone A.">A.FF">H. to de novo methylation of D.A. Nature 448, 714–717 (2007).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.241. L.chner, M., O’Carroll, D., R.a, S./font>., M.chtler, K. & Jenuwein, T. M.thylation of histone A.">A.FF">H. lysine 9 creates a binding site for A.FF">H.1 proteins. Nature 410, 116–120 (2001).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.242. L.hnertz, B. et al. S./font>uv39h-mediated histone A.">A.FF">H. lysine 9 methylation directs D.A.methylation to major satellite repeats at pericentric heterochromatin. Curr. B.ol. 13, 1192–1200 (2003).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.243. S./font>arraf, S./font>. A. & S./font>tancheva, I. M.thyl-CpA.FF">G.binding protein M.font style="background-color:#FFAAFF">B.1 couples histone A.">A.FF">H. methylation at lysine 9 by S./font>A.FF">F.A.A.FF">F.">E.D.font style="background-color:#FFAAFF">B. to D.A.replication and chromatin assembly. M.l. Cell 15, 595–605 (2004).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.244. A.FF">F.A.A.FF">F.">E.sztejn-L.tman, S./font>. et al. D. novo D.A.methylation promoted by A.FF">G.a prevents reprogramming of embryonical.y silenced genes. Nat. S./font>truct. M.l. B.ol. 15, 1176–1183 (2008).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.245. M.rray, K. T.e occurrence of epsilon-N-methyl lysine in histones. B.ochemistry 3, 10–15 (1964).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.246. A.FF">F.lnes, P. O., Jakobsson, M. A.FF">F.A.A.FF">F.">E., D.vydova, A.FF">F.A.A.FF">F.">E., A.FF">H., A. & M.lecki, J. A.C8EA.FF">F.>Protein lysine methylation by seven-beta-strand methyltransferases. B.ochem. J. 473, 1995–2009 (2016).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.247. L.rsen, S./font>. C. et al. Proteome-wide anal.sis of arginine monomethylation reveal. widespread occurrence in human cells. S./font>ci. S./font>ignal.9, rs9 (2016).PubM.d.A.ticle.CA.font style="background-color:#0000CC">S./font>. A.FF">G.ogle S./font>cholar.248. Chuikov, S./font>. et al. R.gulation of p53 activity through lysine methylation. Nature 432, 353–360 (2004).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.249. K.uskouti, A., S./font>cheer, A.FF">F.A.A.FF">F.">E., S./font>taub, A., T.ra, L. & T.lianidis, A.FF">F.A.A.FF">F.">I. A.FF">G.ne-specific modulation of T.font style="background-color:#FFAAFF">A.font style="background-color:#FFA.FF">F.0 function by S./font>A.FF">F.A.A.FF">F.">E.9-mediated methylation. M.l. Cell 14, 175–182 (2004).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.250. A.mstrong, J. A.FF">F., K.ufman, M. A.FF">H., A.FF">H.rrison, D. J. & Clarke, A. R. A.FF">H.gh-frequency developmental.abnormal.ties in p53-deficient mice. Curr. B.ol. 5, 931–936 (1995).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.251. K.ufman, M. A.FF">H. et al. A.al.sis of fused maxillary incisor dentition in p53-deficient exencephal.c mice. J. A.at. 191, 57–64 (1997).PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.252. R.non, A. et al. p53 coordinates cranial.neural.crest cell growth and epithelial.mesenchymal.transition/delamination processes. D.velopment 138, 1827–1838 (2011).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.253. S./font>ah, V. P. et al. A.subset of p53-deficient embryos exhibit exencephal.. Nat. A.FF">G.net. 10, 175–180 (1995).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.254. S./font>aifudeen, Z., D.pp, S./font>. & A.FF">F.A.A.FF">F.">E.-D.hr, S./font>. S./font>. A.role for p53 in terminal.epithelial.cell differentiation. J. Clin. Invest. 109, 1021–1030 (2002).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.255. A.FF">H., A. et al. PR.2 directly methylates A.FF">G.T.font style="background-color:#FFAAFF">A. and represses its transcriptional.activity. A.FF">G.nes D.v. 26, 37–42 (2012).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.256. R.smussen, T. A.FF">L. et al. S./font>myd1 facilitates heart development by antagonizing oxidative and A.FF">F.A.A.FF">F.">E. stress responses. PL.S./font> ONA.FF">F.A.A.FF">F.">E.10, e0121765 (2015).PubM.d.PubM.d Central.A.ticle.CA.font style="background-color:#0000CC">S./font>. A.FF">G.ogle S./font>cholar.257. Pek, J. W., A.and, A. & K.i, T. T.dor domain proteins in development. D.velopment 139, 2255–2266 (2012).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.258. Pengelly, A. R., Copur, O., Jackle, A.FF">H., A.FF">H.rzig, A. & M.ller, J. A.histone mutant reproduces the phenotype caused by loss of histone-modifying factor Polycomb. S./font>cience 339, 698–699 (2013).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.259. M.K.y, D. J. et al./font>. Interrogating the function of metazoan histones using engineered gene clusters. D.v. Cell 32, 373–386 (2015).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.260. V.rmillion, K. L., L.dberg, K. A. & A.FF">G.mmill, L. S./font>. Cytoplasmic protein methylation is essential.for neural.crest migration. J. Cell B.ol. 204, 95–109 (2014).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.261. B.isvert, A.FF">F. M., Chenard, C. A. & R.chard, S./font>. A.C8EA.FF">F.>Protein interfaces in signal.ng regulated by arginine methylation. S./font>ci. S./font>T.font style="background-color:#FFAAFF">K.font style="background-color:#A.FF">F.A.A.FF">F.">E.2005, D.EE">re2 (2005).PubM.d.PubM.d Central. A.FF">G.ogle S./font>cholar.262. X., W. et al. A.transcriptional.switch mediated by cofactor methylation. S./font>cience 294, 2507–2511 (2001).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle.PubM.d Central. A.FF">G.ogle S./font>cholar.263. S./font>hishkova, A.FF">F.A.A.FF">F.">E. et al. A.FF">G.obal.mapping of CA.M. substrates defines enzyme specificity and substrate recognition. Nat. Commun. 8, 15571 (2017).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.264. A.FF">H., S./font>. B. et al. A.C8EA.FF">F.>Protein arginine methyltransferase CA.M. attenuates the paraspeckle-mediated nuclear retention of mR.A. containing IR.font style="background-color:#FFAAFF">A.us. A.FF">G.nes D.v. 29, 630–645 (2015).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.265. A.FF">H.pal.wska, A. et al. CA.M. and paraspeckles regulate pre-implantation mouse embryo development. Cell 175, 1902–1916 (2018).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.266. K.m, D. et al. A.FF">F.A.A.FF">F.">E.zymatic activity is required for the in vivo functions of CA.M.. J. B.ol. Chem. 285, 1147–1152 (2010).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.267. Nimura, K. et al. A.histone A.">A.FF">H. lysine 36 trimethyltransferase links Nkx2-5 to W.lf–A.FF">H.rschhorn syndrome. Nature 460, 287–291 (2009).CA.font style="background-color:#0000CC">S./font>.PubM.d.A.ticle. A.FF">G.ogle S./font>cholar.268. A.FF">K.roki, S./font>. et al. Combined loss of JM.D.A.and JM.D.B.reveal. critical.roles for A.">A.FF">H.K. demethylation in the maintenance of embryonic stem cells and early embryogenesis. S./font>tem Cell R.p. 10, 1340–1354 (2018).CA.font style="background-color:#0000CC">S./font>.A.ticle. A.FF">G.ogle S./font>cholar.269. Neault, M., M.llette, A.FF">F. A., V.gel, A.FF">G., M.chaud-L.vesque, J. & R.chard, S./font>. A.lation of PR.font style="background-color:#A1DAEE">M.6 reveal. a role as a negative transcriptional.regulator of the p53 tumor suppressor. Nucleic A.ids R.s. 40, 9513–9521 (2012).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.270. A.FF">F.A.A.FF">F.">E.hkova, A.FF">F.A.A.FF">F.">E. et al. A.FF">F.A.A.FF">F.">E.A.FF">H. and A.FF">F.A.A.FF">F.">E.A.FF">H. cogovern histone A.">A.FF">H.K.7 trimethylation and are essential.for hair follicle homeostasis and wound repair. A.FF">G.nes D.v. 25, 485–498 (2011).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar.271. Y.tsenko, S./font>. A. et al. D.letion 9q34.3 syndrome: genotype-phenotype correlations and an extended deletion in a patient with features of Opitz C B.E">trigonocephal.. J. M.d. A.FF">G.net. 42, 328–335 (2005).CA.font style="background-color:#0000CC">S./font>.PubM.d.PubM.d Central.A.ticle. A.FF">G.ogle S./font>cholar. D.wnload references .A.knowledgements.R.search in the S./font>hi lab is supported by grants from the US./font> National.Institutes of A.FF">H.al.h (R.1 A.FF">G.117264, R.1 M.font style="background-color:#FFA.FF">H.96066, R.5 CA.10104). Y.S./font>. is an A.erican Cancer S./font>ociety R.search Professor.A.thor information.A.thor notes.A.FF">A.hwini Jambhekar.Present address: D.partment of S./font>ystems B.ology, A.FF">H.rvard M.dical.S./font>chool, B.ston, M.font style="background-color:#FFAAFF">A. US./font>A.A.filiations.Newborn M.dicine, B.ston Children’s A.FF">H.spital. B.ston, M.font style="background-color:#FFAAFF">A. US./font>A.A.FF">A.hwini Jambhekar., A.hinav D.al.. & Y.ng S./font>hi.D.partment of Cell B.ology, A.FF">H.rvard M.dical.S./font>chool, B.ston, M.font style="background-color:#FFAAFF">A. US./font>A.A.FF">A.hwini Jambhekar., A.hinav D.al.. & Y.ng S./font>hi.A.thors.S./font>earch for A.FF">A.hwini Jambhekar in:.PubM.d • . A.FF">G.ogle S./font>cholar .S./font>earch for A.hinav D.al. in:.PubM.d • . A.FF">G.ogle S./font>cholar .S./font>earch for Y.ng S./font>hi in:.PubM.d • . A.FF">G.ogle S./font>cholar .Contributions.A.l authors made substantial.contributions to the discussion of content, wrote the manuscript and edited it before submission. A.FF">A.J. and A.D. al.o researched data for the article.Corresponding authors.Correspondence to A.FF">A.hwini Jambhekar or Y.ng S./font>hi.A.FF">F.A.A.FF">F.">E.hics declarations. Competing interests. Y.S./font>. is a cofounder of Constellation Pharmaceutical. and A.helas T.erapeutics, as well as a consultant for A.tive M.tif, Inc. A.FF">A.J. and A.D. declare no competing interests.A.ditional.information.Peer review information.Nature R.views M.lecular Cell B.ology thanks C. L. and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.Publisher’s note.S./font>pringer Nature remains neutral.with regard to jurisdictional.claims in published maps and institutional.affiliations.S./font>upplementary information.S./font>upplementary information.A.FF">G.ossary.A.FF">G.nomic imprinting M.noal.elic expression of a gene specifical.y from either the maternal.or paternal.copy. A.FF">H.X.genes A.FF">G.nes encoding homeodomain-containing developmental.transcription factors that are arranged in linear arrays and expressed in a spatial.y and temporal.y regulated manner corresponding to their one-dimensional.arrangement al.ng the chromosome. Chromodomain A.C8EA.FF">F.>Protein domain that binds methylated lysine. B.omodomain A.C8EA.FF">F.>Protein domain that binds acetylated lysine. S./font>A.FF">F.A.A.FF">F.">E. domain A.C8EA.FF">F.>Protein domain that typical.y harbours catal.tic methyltransferase activity. Plant homeodomain (PA.FF">H.) fingers Z.nc-finger-containing domain involved in recognizing histone modifications. T.dor domain A.C8EA.FF">F.>Protein domain that recognizes methylated lysines and arginines. CpA.FF">G.islands R.gions of the genome with elevated frequency of CpA.FF">G.dinucleotide, often occurring in gene regulatory regions and often displaying D.A.hypomethylation on cytosine. M.d-blastula transition A.FF">F.A.A.FF">F.">E.bryonic stage at which cells in the blastula switch from rapid cycling between S./font> and M.phases to lengthened cell cycles including A.FF">G. and A.FF">G. phases. T.ophectoderm Cells forming the outer layer of the mammal.an embryo that later give rise to the placenta. Inner cell mass Cluster of undifferentiated cells in the mammal.an embryo that give rise to the fetus. Poised enhancers A.FF">F.A.A.FF">F.">E.hancers that contain A.">A.FF">H.K.me1 and A.">A.FF">H.K.7me3 marks and are unable to activate gene expression but that remain capable of activation in the future. Primed enhancers A. enhancer state that is intermediate between poised and active states. S./font>uch enhancers are characterized by A.">A.FF">H.K.me1 marks and D.A.hypomethylation but are unable to activate gene expression. Z.gotic gene activation A.tivation of transcription from the genome of the embryo, accompanied by clearance of maternal.transcripts. S./font>ex combs In D.osophila melanogaster, a set of mal.-specific bristles on the leg. Position effect variegation V.riation in gene expression levels based on the surrounding genomic context of the gene. Neural.crest cells A.FF">F.A.A.FF">F.">E.bryonic cells that arise from the ectoderm and give rise to multiple tissues, including craniofacial.structures and peripheral.nerves. S./font>ub-ventricular zone R.gion of the brain lining the ventricles that generates neural.and glial.precursors. M.dulloblastoma Paediatric brain tumour, believed to originate from primitive (undifferentiated) neuro-ectodermal.cells, that most commonly arises in the cerebellum during the first decade of life and accounts for approximately 10% of primary brain tumours in children. A.u elements A.FF">F.A.A.FF">F.">S./font>hort stretches of D.A.containing the A.uI restriction site that are repeated millions of times throughout the human genome. A.FF">F.A.A.FF">F.">E.bryoid bodies A.gregates of pluripotent cells that contain cells differentiating towards each of the three germ layers. M.crocephal. R.duced head circumference. Protocadherins A.FF">F.mily of cell adhesion proteins important for the development of neurons.R.ghts and permissions.R.prints and Permissions.A.out this article.A.cepted.24 M.y 2019Published.02 July 2019D.I.https://doi.org/10.1038/s41580-019-0151-1.
From:
系统抽取对象
人物     
(3)
(1)
(1)
(1)
(36)
(1)
(2)
(2)
(1)
(2)
(1)
(16)
(3)
(1)
(5)
(2)
(1)
(1)
(1)
(1)
(2)
(1)
(1)
(25)
(1)
(1)
(1)
(1)
(1)
(1)
(2)
(7)
(37)
(1)
(1)
(1)
(3)
(1)
(1)
(1)
(1)
(3)
(1)
(1)
(1)
(1)
(1)
(2)
(1)
(87)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(24)
(1)
(13)
(1)
(1)
(1)
(1)
(1)
(1)
(20)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(3)
(2)
(19)
(1)
(1)
(6)
(2)
(1)
(4)
(1)
(10)
(1)
(1)
(8)
(5)
(10)
(1)
(1)
(4)
(1)
(1)
(1)
(1)
(1)
(2)
(8)
(1)
(6)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(2)
(1)
(2)
(1)
(2)
(1)
(1)
(5)
(1)
(1)
(6)
(9)
(1)
(1)
(1)
(1)
(3)
(18)
(1)
(2)
(1)
(1)
(1)
(2)
(1)
(1)
(34)
(1)
(1)
(1)
(1)
(3)
(1)
(2)
(1)
(1)
(21)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(4)
(1)
(1)
(3)
(2)
(23)
(12)
(1)
(3)
(1)
(1)
(27)
(1)
(1)
(1)
(5)
(1)
(11)
(7)
(1)
(2)
(52)
(81)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(326)
(1)
(1)
(2)
(1)
(5)
(1)
(1)
(1)
(1)
(1)
(3)
(1)
(1)
(1)
(3)
(2)
(1)
(1)
(1)
(1)
(2)
(3)
(1)
(2)
(3)
(1)
(1)
(1)
(2)
(1)
(1)
(1)
(1)
(1)
(13)
(1)
(7)
(1)
(2)
(6)
(2)
(2)
(2)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(3)
(2)
(1)
(11)
(11)
(11)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(3)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(20)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(3)
(1)
(1)
(1)
(2)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(4)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(3)
(1)
(1)
(1)
(3)
(3)
(1)
(4)
(1)
(2)
(1)
(1)
(3)
(1)
(1)
(1)
(3)
(1)
(1)
(2)
(1)
(1)
(1)
(1)
(15)
(20)
(1)
(1)
(1)
(1)
(1)
(1)
(6)
(1)
(11)
(11)
(1)
(11)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(3)
(1)
(1)
(1)
(1)
(10)
(2)
(1)
(2)
(10)
(1)
(1)
(90)
(1)
(1)
(1)
(1)
(1)
(2)
(7)
(1)
(1)
(1)
(6)
(1)
(2)
(2)
(1)
(1)
(1)
(1)
(11)
(1)
(1)
(2)
(1)
(3)
(1)
(1)
(1)
(1)