Abstract
DNA methylation (DNAme) and histone post-translational modifications (PTMs) have important roles in transcriptional regulation. Although many reports have characterized the functions of such chromatin marks in isolation, recent genome-wide studies reveal surprisingly complex interactions between them. Here, we focus on the interplay between DNAme and methylation of specific lysine residues on the histone H3 tail. We describe the impact of genetic perturbation of the relevant methyltransferases in the mouse on the landscape of chromatin marks as well as the transcriptome. In addition, we discuss the specific neurodevelopmental growth syndromes and cancers resulting from pathogenic mutations in the human orthologues of these genes. Integrating these observations underscores the fundamental importance of crosstalk between DNA and histone H3 methylation in development and disease.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Greenberg, M. V. C. & Bourc’his, D. The diverse roles of DNA methylation in mammalian development and disease. Nat. Rev. Mol. Cell Biol. 20, 590–607 (2019).
Jenuwein, T. & Allis, C. D. Translating the histone code. Science 293, 1074–1080 (2001).
Hyun, K., Jeon, J., Park, K. & Kim, J. Writing, erasing and reading histone lysine methylations. Exp. Mol. Med. 49, e324 (2017).
Jambhekar, A., Dhall, A. & Shi, Y. Roles and regulation of histone methylation in animal development. Nat. Rev. Mol. Cell Biol. 20, 625–641 (2019).
Li, J., Ahn, J. H. & Wang, G. G. Understanding histone H3 lysine 36 methylation and its deregulation in disease. Cell Mol. Life Sci. 76, 2899–2916 (2019).
Kimura, H. Histone modifications for human epigenome analysis. J. Hum. Genet. 58, 439–445 (2013).
Cooper, D. N., Taggart, M. H. & Bird, A. P. Unmethylated domains in vertebrate DNA. Nucleic Acids Res. 11, 647–658 (1983).
Bird, A., Taggart, M., Frommer, M., Miller, O. J. & Macleod, D. A fraction of the mouse genome that is derived from islands of nonmethylated, CpG-rich DNA. Cell 40, 91–99 (1985).
Weber, M. et al. Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nat. Genet. 39, 457–466 (2007).
Meissner, A. et al. Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454, 766–770 (2008).
Smallwood, S. A. & Kelsey, G. De novo DNA methylation: a germ cell perspective. Trends Genet. 28, 33–42 (2012).
Edwards, J. R. et al. Chromatin and sequence features that define the fine and gross structure of genomic methylation patterns. Genome Res. 20, 972–980 (2010).
Fu, K., Bonora, G. & Pellegrini, M. Interactions between core histone marks and DNA methyltransferases predict DNA methylation patterns observed in human cells and tissues. Epigenetics 15, 272–282 (2019).
Lynch, M. D. et al. An interspecies analysis reveals a key role for unmethylated CpG dinucleotides in vertebrate Polycomb complex recruitment. EMBO J. 31, 317–329 (2011).
Appanah, R., Dickerson, D. R., Goyal, P., Groudine, M. & Lorincz, M. C. An unmethylated 3′ promoter-proximal region is required for efficient transcription initiation. PLoS Genet. 3, 241–253 (2007).
Ooi, S. K. T. et al. DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature 448, 714–717 (2007). This study shows that the cysteine-rich domain (later termed the ADD domain) of DNMT3L selectively interacts with unmethylated H3K4.
Zhang, Y. et al. Chromatin methylation activity of Dnmt3a and Dnmt3a/3L is guided by interaction of the ADD domain with the histone H3 tail. Nucleic Acids Res. 38, 4246–4253 (2010).
Otani, J. et al. Structural basis for recognition of H3K4 methylation status by the DNA methyltransferase 3A ATRX-DNMT3-DNMT3L domain. EMBO Rep. 10, 1235–1241 (2009).
Li, B.-Z. et al. Histone tails regulate DNA methylation by allosterically activating de novo methyltransferase. Cell Res. 21, 1172–1181 (2011).
Hu, J.-L. et al. The N-terminus of histone H3 is required for de novo DNA methylation in chromatin. Proc. Natl Acad. Sci. USA 106, 22187–22192 (2009).
Xu, T.-H. et al. Structure of nucleosome-bound DNA methyltransferases DNMT3A and DNMT3B. Nature 586, 151–155 (2020).
Zeng, Y. et al. The inactive Dnmt3b3 isoform preferentially enhances Dnmt3b-mediated DNA methylation. Genes Dev. 34, 1546–1558 (2020).
Guo, X. et al. Structural insight into autoinhibition and histone H3-induced activation of DNMT3A. Nature 517, 640–644 (2015). This study reveals that binding of the DNMT3A ADD domain to unmodified H3K4 relieves its autoinhibitory interaction with the catalytic domain.
Liu, X. et al. Distinct features of H3K4me3 and H3K27me3 chromatin domains in pre-implantation embryos. Nature 537, 558–562 (2016).
Singh, P. et al. De novo DNA methylation in the male germ line occurs by default but is excluded at sites of H3K4 methylation. Cell Rep. 4, 205–219 (2013).
Zhang, B. et al. Allelic reprogramming of the histone modification H3K4me3 in early mammalian development. Nature 537, 553–557 (2016).
Hammoud, S. S. et al. Chromatin and transcription transitions of mammalian adult germline stem cells and spermatogenesis. Cell Stem Cell 15, 239–253 (2014).
Greenfield, R. et al. Role of transcription complexes in the formation of the basal methylation pattern in early development. Proc. Natl Acad. Sci. USA 115, 10387–10391 (2018).
Mikkelsen, T. S. et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448, 553–560 (2007).
Mohn, F. et al. Lineage-specific polycomb targets and de novo DNA methylation define restriction and potential of neuronal progenitors. Mol. Cell 30, 755–766 (2008).
Ginno, P. A. et al. A genome-scale map of DNA methylation turnover identifies site-specific dependencies of DNMT and TET activity. Nat. Commun. 11, 2680 (2020).
Noh, K.-M. et al. Engineering of a histone-recognition domain in Dnmt3a alters the epigenetic landscape and phenotypic features of mouse ESCs. Mol. Cell 59, 89–103 (2015). This study reveals aberrant DNMT3A targeting to H3K4me3-marked promoters due to a mutation in the ADD domain, rendering it insensitive to the H3K4me state.
Hagarman, J. A., Motley, M. P., Kristjansdottir, K. & Soloway, P. D. Coordinate regulation of DNA methylation and H3K27me3 in mouse embryonic stem cells. PLoS ONE 8, e53880 (2013).
Li, Y. et al. Genome-wide analyses reveal a role of Polycomb in promoting hypomethylation of DNA methylation valleys. Genome Biol. 19, 18 (2018).
Hanna, C. W. et al. MLL2 conveys transcription-independent H3K4 trimethylation in oocytes. Nat. Struct. Mol. Biol. 25, 73–82 (2018).
Douillet, D. et al. Uncoupling histone H3K4 trimethylation from developmental gene expression via an equilibrium of COMPASS, Polycomb and DNA methylation. Nat. Genet. 52, 615–625 (2020).
Grosswendt, S. et al. Epigenetic regulator function through mouse gastrulation. Nature 584, 102–108 (2020).
Hernandez, C. et al. Dppa2/4 facilitate epigenetic remodeling during reprogramming to pluripotency. Cell Stem Cell 23, 396–411 (2018).
Eckersley-Maslin, M. A. et al. Epigenetic priming by Dppa2 and 4 in pluripotency facilitates multi-lineage commitment. Nat. Struct. Mol. Biol. 27, 696–705 (2020).
Gretarsson, K. H. & Hackett, J. A. Dppa2 and Dppa4 counteract de novo methylation to establish a permissive epigenome for development. Nat. Struct. Mol. Biol. 27, 706–716 (2020).
Collins, B. E., Greer, C. B., Coleman, B. C. & Sweatt, J. D. Histone H3 lysine K4 methylation and its role in learning and memory. Epigenetics Chromatin 12, 7 (2019).
Cenik, B. K. & Shilatifard, A. COMPASS and SWI/SNF complexes in development and disease. Nat. Rev. Genet. 22, 38–58 (2020).
Krzyzewska, I. M. et al. A genome-wide DNA methylation signature for SETD1B-related syndrome. Clin. Epigenetics 11, 156 (2019).
Aref-Eshghi, E. et al. Evaluation of DNA methylation episignatures for diagnosis and phenotype correlations in 42 Mendelian neurodevelopmental disorders. Am. J. Hum. Genet. 106, 356–370 (2020).
Labonne, J. D. J. et al. An atypical 12q24.31 microdeletion implicates six genes including a histone demethylase KDM2B and a histone methyltransferase SETD1B in syndromic intellectual disability. Hum. Genet. 135, 757–771 (2016).
Butcher, D. T. et al. CHARGE and Kabuki syndromes: gene-specific DNA methylation signatures identify epigenetic mechanisms linking these clinically overlapping conditions. Am. J. Hum. Genet. 100, 773–788 (2017).
Sobreira, N. et al. Patients with a Kabuki syndrome phenotype demonstrate DNA methylation abnormalities. Eur. J. Hum. Genet. 25, 1335–1344 (2017).
Aref-Eshghi, E. et al. The defining DNA methylation signature of Kabuki syndrome enables functional assessment of genetic variants of unknown clinical significance. Epigenetics 12, 923–933 (2017).
Ng, S. B. et al. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat. Genet. 42, 790–793 (2010).
Steiner, C. E. & Marques, A. P. Growth deficiency, mental retardation and unusual facies. Clin. Dysmorphol. 9, 155 (2000).
Jones, W. D. et al. De novo mutations in MLL cause wiedemann-steiner syndrome. Am. J. Hum. Genet. 91, 358–364 (2012).
Rao, R. C. & Dou, Y. Hijacked in cancer: the KMT2 (MLL) family of methyltransferases. Nat. Rev. Cancer 15, 334–346 (2015).
Saksouk, N., Simboeck, E. & Déjardin, J. Constitutive heterochromatin formation and transcription in mammals. Epigenetics Chromatin 8, 3 (2015).
Nicetto, D. & Zaret, K. S. Role of H3K9me3 heterochromatin in cell identity establishment and maintenance. Curr. Opin. Genet. Dev. 55, 1–10 (2019).
Bruno, M., Mahgoub, M. & Macfarlan, T. S. The arms race between KRAB–zinc finger proteins and endogenous retroelements and its impact on mammals. Annu. Rev. Genet. 53, 393–416 (2019).
Bulut-Karslioglu, A. et al. Suv39h-dependent H3K9me3 marks intact retrotransposons and silences LINE elements in mouse embryonic stem cells. Mol. Cell 55, 277–290 (2014).
Jackson, J. P., Lindroth, A. M., Cao, X. & Jacobsen, S. E. Control of CpNpG DNA methylation by the KRYPTONITE histone H3 methyltransferase. Nature 416, 556–560 (2002).
Tamaru, H. & Selker, E. U. A histone H3 methyltransferase controls DNA methylation in Neurospora crassa. Nature 414, 277–283 (2001).
Sharif, J. et al. The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA. Nature 450, 908–912 (2007). This study, together with Bostick et al. (2007), shows that UHRF1 binds to hemimethylated DNA, facilitates DNMT1 chromatin binding and thereby ensures faithful maintenance of DNAme.
Bostick, M. et al. UHRF1 plays a role in maintaining DNA methylation in mammalian cells. Science 317, 1760–1764 (2007).
Unoki, M., Nishidate, T. & Nakamura, Y. ICBP90, an E2F-1 target, recruits HDAC1 and binds to methyl-CpG through its SRA domain. Oncogene 23, 7601–7610 (2004).
Avvakumov, G. V. et al. Structural basis for recognition of hemi-methylated DNA by the SRA domain of human UHRF1. Nature 455, 822–825 (2008).
Arita, K., Ariyoshi, M., Tochio, H., Nakamura, Y. & Shirakawa, M. Recognition of hemi-methylated DNA by the SRA protein UHRF1 by a base-flipping mechanism. Nature 455, 818–821 (2008).
Hashimoto, H. et al. The SRA domain of UHRF1 flips 5-methylcytosine out of the DNA helix. Nature 455, 826–829 (2008).
Harrison, J. S. et al. Hemi-methylated DNA regulates DNA methylation inheritance through allosteric activation of H3 ubiquitylation by UHRF1. eLife 5, e17101 (2016).
Vaughan, R. M. et al. Chromatin structure and its chemical modifications regulate the ubiquitin ligase substrate selectivity of UHRF1. Proc. Natl Acad. Sci. USA 115, 8775–8780 (2018).
Vaughan, R. M., Rothbart, S. B. & Dickson, B. M. The finger loop of the SRA domain in the E3 ligase UHRF1 is a regulator of ubiquitin targeting and is required for the maintenance of DNA methylation. J. Biol. Chem. 294, 15724–15732 (2019).
Karagianni, P., Amazit, L., Qin, J. & Wong, J. ICBP90, a novel methyl K9 H3 binding protein linking protein ubiquitination with heterochromatin formation. Mol. Cell Biol. 28, 705–717 (2008).
Nishiyama, A. et al. Uhrf1-dependent H3K23 ubiquitylation couples maintenance DNA methylation and replication. Nature 502, 249–253 (2013).
Qin, W. et al. DNA methylation requires a DNMT1 ubiquitin interacting motif (UIM) and histone ubiquitination. Cell Res. 25, 911–929 (2015).
Karg, E. et al. Ubiquitome analysis reveals PCNA-associated factor 15 (PAF15) as a specific ubiquitination target of UHRF1 in embryonic stem cells. J. Mol. Biol. 429, 3814–3824 (2017).
Ishiyama, S. et al. Structure of the Dnmt1 reader module complexed with a unique two-mono-ubiquitin mark on histone H3 reveals the basis for DNA methylation maintenance. Mol. Cell 68, 350–360 (2017).
González-Magaña, A. et al. Double monoubiquitination modifies the molecular recognition properties of p15 PAF promoting binding to the reader module of Dnmt1. ACS Chem. Biol. 14, 2315–2326 (2019).
Nishiyama, A. et al. Two distinct modes of DNMT1 recruitment ensure stable maintenance DNA methylation. Nat. Commun. 11, 1222 (2020).
Li, E., Bestor, T. H. & Jaenisch, R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69, 915–926 (1992).
Bartke, T. et al. Nucleosome-interacting proteins regulated by DNA and histone methylation. Cell 143, 470–484 (2010).
Nady, N. et al. Recognition of multivalent histone states associated with heterochromatin by UHRF1 protein. J. Biol. Chem. 286, 24300–24311 (2011).
Rothbart, S. B. et al. Association of UHRF1 with methylated H3K9 directs the maintenance of DNA methylation. Nat. Struct. Mol. Biol. 19, 1155–1160 (2012). This study indicates a role for the interaction between the UHRF1 TTD domain and H3K9me3 in DNMT1-mediated maintenance DNAme.
Arita, K. et al. Recognition of modification status on a histone H3 tail by linked histone reader modules of the epigenetic regulator UHRF1. Proc. Natl Acad. Sci. USA 109, 12950–12955 (2012).
Xie, S., Jakoncic, J. & Qian, C. UHRF1 double tudor domain and the adjacent PHD finger act together to recognize K9me3-containing histone H3 tail. J. Mol. Biol. 415, 318–328 (2012).
Rothbart, S. B. et al. Multivalent histone engagement by the linked tandem Tudor and PHD domains of UHRF1 is required for the epigenetic inheritance of DNA methylation. Genes Dev. 27, 1288–1298 (2013).
Cheng, J. et al. Structural insight into coordinated recognition of trimethylated histone H3 lysine 9 (H3K9me3) by the plant homeodomain (PHD) and tandem tudor domain (TTD) of UHRF1 (ubiquitin-like, containing PHD and RING finger domains, 1) protein. J. Biol. Chem. 288, 1329–1339 (2013).
Tauber, M. et al. Alternative splicing and allosteric regulation modulate the chromatin binding of UHRF1. Nucleic Acids Res. 48, 7728–7747 (2020).
Liu, X. et al. UHRF1 targets DNMT1 for DNA methylation through cooperative binding of hemi-methylated DNA and methylated H3K9. Nat. Commun. 4, 1563 (2013).
Bashtrykov, P., Jankevicius, G., Jurkowska, R. Z., Ragozin, S. & Jeltsch, A. The UHRF1 protein stimulates the activity and specificity of the maintenance DNA methyltransferase DNMT1 by an allosteric mechanism. J. Biol. Chem. 289, 4106–4115 (2013).
Peters, A. H. F. M. et al. Partitioning and plasticity of repressive histone methylation states in mammalian chromatin. Mol. Cell 12, 1577–1589 (2003).
Saksouk, N. et al. Redundant mechanisms to form silent chromatin at pericentromeric regions rely on BEND3 and DNA methylation. Mol. Cell 56, 580–594 (2014).
Han, M. et al. A role for LSH in facilitating DNA methylation by DNMT1 through enhancing UHRF1 chromatin association. Nucleic Acids Res. 48, 12116–12134 (2020).
Ming, X. et al. Kinetics and mechanisms of mitotic inheritance of DNA methylation and their roles in aging-associated methylome deterioration. Cell Res. 30, 980–996 (2020).
Ren, W. et al. Direct readout of heterochromatic H3K9me3 regulates DNMT1-mediated maintenance DNA methylation. Proc. Natl Acad. Sci. USA 117, 18439–18447 (2020). This study uncovers a direct interaction between the RFTS domain of DNMT1 and H3K9me3.
Ren, W. et al. DNMT1 reads heterochromatic H4K20me3 to reinforce LINE-1 DNA methylation. Nat. Commun. 12, 2490 (2021).
Leung, D. et al. Regulation of DNA methylation turnover at LTR retrotransposons and imprinted loci by the histone methyltransferase Setdb1. Proc. Natl Acad. Sci. USA 111, 6690–6695 (2014).
Liu, S. et al. Setdb1 is required for germline development and silencing of H3K9me3-marked endogenous retroviruses in primordial germ cells. Genes Dev. 28, 2041–2055 (2014).
Lane, N. et al. Resistance of IAPs to methylation reprogramming may provide a mechanism for epigenetic inheritance in the mouse. Genesis 35, 88–93 (2003). This study is the first of many to show that specific TEs are resistant to DNA demethylation during epigenetic reprogramming in germ cells and the pre-implantation embryo.
Popp, C. et al. Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency. Nature 463, 1101–1105 (2010).
Guibert, S., Forné, T. & Weber, M. Global profiling of DNA methylation erasure in mouse primordial germ cells. Genome Res. 22, 633–641 (2012).
Seisenberger, S. et al. The dynamics of genome-wide DNA methylation reprogramming in mouse primordial germ cells. Mol. Cell 48, 849–862 (2012). This study extensively characterizes the dynamics of DNAme in early germ cell development, starting from the epiblast to E16.5 female and male germ cells.
Kobayashi, H. et al. High-resolution DNA methylome analysis of primordial germ cells identifies gender-specific reprogramming in mice. Genome Res. 23, 616–627 (2013).
Quenneville, S. et al. In embryonic stem cells, ZFP57/KAP1 recognize a methylated hexanucleotide to affect chromatin and DNA methylation of imprinting control regions. Mol. Cell 44, 361–372 (2011).
Takahashi, N. et al. ZNF445 is a primary regulator of genomic imprinting. Genes Dev. 33, 49–54 (2019).
Habibi, E. et al. Whole-genome bisulfite sequencing of two distinct interconvertible DNA methylomes of mouse embryonic stem cells. Cell Stem Cell 13, 360–369 (2013).
von Meyenn, F. et al. Comparative principles of DNA methylation reprogramming during human and mouse in vitro primordial germ cell specification. Dev. Cell 39, 104–115 (2016).
Biniszkiewicz, D. et al. Dnmt1 overexpression causes genomic hypermethylation, loss of imprinting, and embryonic lethality. Mol. Cell Biol. 22, 2124–2135 (2002).
Hirasawa, R. et al. Maternal and zygotic Dnmt1 are necessary and sufficient for the maintenance of DNA methylation imprints during preimplantation development. Genes Dev. 22, 1607–1616 (2008).
Maenohara, S. et al. Role of UHRF1 in de novo DNA methylation in oocytes and maintenance methylation in preimplantation embryos. PLoS Genet. 13, e1007042 (2017).
Min, B., Park, J. S., Jeong, Y. S., Jeon, K. & Kang, Y.-K. Dnmt1 binds and represses genomic retroelements via DNA methylation in mouse early embryos. Nucleic Acids Res. 48, 8431–8444 (2020).
Dahlet, T. et al. Genome-wide analysis in the mouse embryo reveals the importance of DNA methylation for transcription integrity. Nat. Commun. 11, 3153 (2020).
Wang, Q. et al. Imprecise DNMT1 activity coupled with neighbor-guided correction enables robust yet flexible epigenetic inheritance. Nat. Genet. 52, 828–839 (2020).
Haggerty, C. et al. Dnmt1 has de novo activity targeted to transposable elements. Nat. Struct. Mol. Biol. 28, 594–603 (2021).
He, J. et al. Transposable elements are regulated by context-specific patterns of chromatin marks in mouse embryonic stem cells. Nat. Commun. 10, 34 (2019).
Dong, J. et al. UHRF1 suppresses retrotransposons and cooperates with PRMT5 and PIWI proteins in male germ cells. Nat. Commun. 10, 4705 (2019).
von Meyenn, F. et al. Impairment of DNA methylation maintenance is the main cause of global demethylation in naive embryonic stem cells. Mol. Cell 62, 848–861 (2016).
Funaki, S. et al. Inhibition of maintenance DNA methylation by Stella. Biochem. Biophys. Res. Commun. 453, 455–460 (2014).
Du, W. et al. Stella protein facilitates DNA demethylation by disrupting the chromatin association of the RING finger-type E3 ubiquitin ligase UHRF1. J. Biol. Chem. 294, 8907–8917 (2019).
Sato, M. et al. Identification of PGC7, a new gene expressed specifically in preimplantation embryos and germ cells. Mech. Dev. 113, 91–94 (2002).
Saitou, M., Barton, S. C. & Surani, M. A. A molecular programme for the specification of germ cell fate in mice. Nature 418, 293–300 (2002).
Li, Y. et al. Stella safeguards the oocyte methylome by preventing de novo methylation mediated by DNMT1. Nature 564, 136–140 (2018).
Han, L., Ren, C., Zhang, J., Shu, W. & Wang, Q. Differential roles of Stella in the modulation of DNA methylation during oocyte and zygotic development. Cell Discov. 5, 9 (2019).
Mulholland, C. B. et al. Recent evolution of a TET-controlled and DPPA3/STELLA-driven pathway of passive DNA demethylation in mammals. Nat. Commun. 11, 5972 (2020).
Nakashima, H. et al. Effects of Dppa3 on DNA methylation dynamics during primordial germ cell development in mice. Biol. Reprod. 88, 125 (2013).
Zhao, Q. et al. Dissecting the precise role of H3K9 methylation in crosstalk with DNA maintenance methylation in mammals. Nat. Commun. 7, 12464 (2016).
Smith, Z. D. et al. Epigenetic restriction of extraembryonic lineages mirrors the somatic transition to cancer. Nature 549, 543–547 (2017).
Molaro, A. et al. Two waves of de novo methylation during mouse germ cell development. Genes Dev. 28, 1544–1549 (2014).
Kubo, N. et al. DNA methylation and gene expression dynamics during spermatogonial stem cell differentiation in the early postnatal mouse testis. BMC Genomics 16, 624 (2015).
Shirane, K., Miura, F., Ito, T. & Lorincz, M. C. NSD1-deposited H3K36me2 directs de novo methylation in the mouse male germline and counteracts Polycomb-associated silencing. Nat. Genet. 52, 1088–1098 (2020).
Ohta, H. et al. In vitro expansion of mouse primordial germ cell-like cells recapitulates an epigenetic blank slate. EMBO J. 36, 1888–1907 (2017).
Sakai, Y., Suetake, I., Shinozaki, F., Yamashina, S. & Tajima, S. Co-expression of de novo DNA methyltransferases Dnmt3a2 and Dnmt3L in gonocytes of mouse embryos. Gene Expr. Patterns 5, 231–237 (2004).
Yamanaka, S. et al. Broad heterochromatic domains open in gonocyte development prior to de novo DNA methylation. Dev. Cell 51, 21–34 (2019). Employing ATAC-seq in male germ cells, this study reveals an increase in chromatin accessibility in heterochromatic regions at E17.5 versus E13.5.
Soldi, M. & Bonaldi, T. The proteomic investigation of chromatin functional domains reveals novel synergisms among distinct heterochromatin components. Mol. Cell Proteom. 12, 764–780 (2013).
Stroud, H. et al. Early-life gene expression in neurons modulates lasting epigenetic states. Cell 171, 1151–1164 (2017).
Köhler, F. et al. Epigenetic deregulation of lamina-associated domains in Hutchinson–Gilford progeria syndrome. Genome Med. 12, 46 (2020).
Bachman, K. E., Rountree, M. R. & Baylin, S. B. Dnmt3a and Dnmt3b are transcriptional repressors that exhibit unique localization properties to heterochromatin. J. Biol. Chem. 276, 32282–32287 (2001).
Chen, T., Ueda, Y., Dodge, J. E., Wang, Z. & Li, E. Establishment and maintenance of genomic methylation patterns in mouse embryonic stem cells by Dnmt3a and Dnmt3b. Mol. Cell Biol. 23, 5594–5605 (2003).
Dukatz, M. et al. H3K36me2/3 binding and DNA binding of the DNA methyltransferase DNMT3A PWWP domain both contribute to its chromatin interaction. J. Mol. Biol. 431, 5063–5074 (2019).
Hiragami-Hamada, K. et al. Dynamic and flexible H3K9me3 bridging via HP1β dimerization establishes a plastic state of condensed chromatin. Nat. Commun. 7, 11310 (2016).
Healton, S. E. et al. H1 linker histones silence repetitive elements by promoting both histone H3K9 methylation and chromatin compaction. Proc. Natl Acad. Sci. USA 117, 14251–14258 (2020).
Magaraki, A. et al. Silencing markers are retained on pericentric heterochromatin during murine primordial germ cell development. Epigenetics Chromatin 10, 11 (2017).
Rowbotham, S. P. et al. Maintenance of silent chromatin through replication requires SWI/SNF-like chromatin remodeler SMARCAD1. Mol. Cell 42, 285–296 (2011).
Navarro, C., Lyu, J., Katsori, A.-M., Caridha, R. & Elsässer, S. J. An embryonic stem cell-specific heterochromatin state promotes core histone exchange in the absence of DNA accessibility. Nat. Commun. 11, 5095 (2020).
Lorincz, M. C., Schübeler, D., Hutchinson, S. R., Dickerson, D. R. & Groudine, M. DNA methylation density influences the stability of an epigenetic imprint and Dnmt3a/b-independent de novo methylation. Mol. Cell Biol. 22, 7572–7580 (2002).
Hermann, A., Goyal, R. & Jeltsch, A. The Dnmt1 DNA-(cytosine-C5)-methyltransferase methylates DNA processively with high preference for hemimethylated target sites. J. Biol. Chem. 279, 48350–48359 (2004).
Lister, R. et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462, 315–322 (2009).
Schroeder, D. I. et al. The human placenta methylome. Proc. Natl Acad. Sci. USA 110, 6037–6042 (2013).
He, Y. et al. Spatiotemporal DNA methylome dynamics of the developing mouse fetus. Nature 583, 752–759 (2020).
Zhou, W. et al. DNA methylation loss in late-replicating domains is linked to mitotic cell division. Nat. Genet. 50, 591–602 (2018).
Salhab, A. et al. A comprehensive analysis of 195 DNA methylomes reveals shared and cell-specific features of partially methylated domains. Genome Biol. 19, 150 (2018).
Berman, B. P. et al. Regions of focal DNA hypermethylation and long-range hypomethylation in colorectal cancer coincide with nuclear lamina-associated domains. Nat. Genet. 44, 40–46 (2011).
Hon, G. C. et al. Global DNA hypomethylation coupled to repressive chromatin domain formation and gene silencing in breast cancer. Genome Res. 22, 246–258 (2012).
Hansen, K. D. et al. Increased methylation variation in epigenetic domains across cancer types. Nat. Genet. 43, 768–775 (2011).
Hovestadt, V. et al. Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing. Nature 510, 537–541 (2014).
Timp, W. et al. Large hypomethylated blocks as a universal defining epigenetic alteration in human solid tumors. Genome Med. 6, 61 (2014).
Decato, B. E. et al. Characterization of universal features of partially methylated domains across tissues and species. Epigenetics Chromatin 13, 39 (2020).
Wagner, E. J. & Carpenter, P. B. Understanding the language of Lys36 methylation at histone H3. Nat. Rev. Mol. Cell Biol. 13, 115–126 (2012).
Edmunds, J. W., Mahadevan, L. C. & Clayton, A. L. Dynamic histone H3 methylation during gene induction: HYPB/Setd2 mediates all H3K36 trimethylation. EMBO J. 27, 406–420 (2008).
Yoh, S. M., Lucas, J. S. & Jones, K. A. The Iws1:Spt6:CTD complex controls cotranscriptional mRNA biosynthesis and HYPB/Setd2-mediated histone H3K36 methylation. Genes Dev. 22, 3422–3434 (2008).
Dhayalan, A. et al. The Dnmt3a PWWP domain reads histone 3 lysine 36 trimethylation and guides DNA methylation. J. Biol. Chem. 285, 26114–26120 (2010).
Baubec, T. et al. Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation. Nature 520, 243–247 (2015).
Weinberg, D. N. et al. The histone mark H3K36me2 recruits DNMT3A and shapes the intergenic DNA methylation landscape. Nature 573, 281–286 (2019). This study reveals that the PWWP domain of DNMT3A interacts with NSD1-mediated H3K36me2 and is required for DNAme at intergenic regions.
Xu, W. et al. DNMT3A reads and connects histone H3K36me2 to DNA methylation. Protein Cell 11, 150–154 (2020).
Jin, B. et al. Linking DNA methyltransferases to epigenetic marks and nucleosome structure genome-wide in human tumor cells. Cell Rep. 2, 1411–1424 (2012).
Morselli, M. et al. In vivo targeting of de novo DNA methylation by histone modifications in yeast and mouse. eLife 4, e06205 (2015).
Xu, Q. et al. SETD2 regulates the maternal epigenome, genomic imprinting and embryonic development. Nat. Genet. 51, 844–856 (2019).
Sotos, J. F., Dodge, P. R., Muirhead, D., Crawford, J. D. & Talbot, N. B. Cerebral gigantism in childhood: a syndrome of excessively rapid growth with acromegalic features and a nonprogressive neurologic disorder. N. Engl. J. Med. 271, 109–116 (1964).
Kurotaki, N. et al. Haploinsufficiency of NSD1 causes Sotos syndrome. Nat. Genet. 30, 365–366 (2002).
Qiao, Q. et al. The structure of NSD1 reveals an autoregulatory mechanism underlying histone H3K36 methylation. J. Biol. Chem. 286, 8361–8368 (2010).
Choufani, S. et al. NSD1 mutations generate a genome-wide DNA methylation signature. Nat. Commun. 6, 10207 (2015).
Tatton-Brown, K. et al. Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability. Nat. Genet. 46, 385–388 (2014).
Jeffries, A. R. et al. Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging. Genome Res. 29, 1057–1066 (2019).
Luscan, A. et al. Mutations in SETD2 cause a novel overgrowth condition. J. Med. Genet. 51, 512–517 (2014).
Lumish, H. S., Wynn, J., Devinsky, O. & Chung, W. K. Brief report: SETD2 mutation in a child with autism, intellectual disabilities and epilepsy. J. Autism Dev. Disord. 45, 3764–3770 (2015).
Xu, G.-L. et al. Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature 402, 187–191 (1999).
Heyn, H. et al. Whole-genome bisulfite DNA sequencing of a DNMT3B mutant patient. Epigenetics 7, 542–550 (2012).
Gatto, S. et al. ICF-specific DNMT3B dysfunction interferes with intragenic regulation of mRNA transcription and alternative splicing. Nucleic Acids Res. 45, 5739–5756 (2017).
Stec, I. et al. WHSC1, a 90 kb SET domain-containing gene, expressed in early development and homologous to a Drosophila dysmorphy gene maps in the wolf-hirschhorn syndrome critical region and is fused to IgH in t(1;14) multiple myeloma. Hum. Mol. Genet. 7, 1071–1082 (1998).
Rayasam, G. V. et al. NSD1 is essential for early post-implantation development and has a catalytically active SET domain. EMBO J. 22, 3153–3163 (2003).
Nimura, K. et al. A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to Wolf–Hirschhorn syndrome. Nature 460, 287–291 (2009).
Kuo, A. J. et al. NSD2 links dimethylation of histone h3 at lysine 36 to oncogenic programming. Mol. Cell 44, 609–620 (2011).
Yang, Z., Jones, A., Widschwendter, M. & Teschendorff, A. E. An integrative pan-cancer-wide analysis of epigenetic enzymes reveals universal patterns of epigenomic deregulation in cancer. Genome Biol. 16, 140 (2015).
Sendžikaitė, G., Hanna, C. W., Stewart-Morgan, K. R., Ivanova, E. & Kelsey, G. A DNMT3A PWWP mutation leads to methylation of bivalent chromatin and growth retardation in mice. Nat. Commun. 10, 1884 (2019).
Heyn, P. et al. Gain-of-function DNMT3A mutations cause microcephalic dwarfism and hypermethylation of Polycomb-regulated regions. Nat. Genet. 51, 96–105 (2019). This study identified a pathogenic GoF mutation in the PWWP domain of DNMT3A in patients with microcephalic dwarfism that abrogates binding to H3K36me2/me3 and leads to altered DNAme.
Rabin, R. et al. Genotype-phenotype correlation at codon 1740 of SETD2. Am. J. Med. Genet. A 182, 2037–2048 (2020).
Rosenfeld, J. A. et al. Further evidence of contrasting phenotypes caused by reciprocal deletions and duplications: duplication of nsd1 causes growth retardation and microcephaly. Mol. Syndromol. 3, 247–254 (2013).
Dikow, N. et al. The phenotypic spectrum of duplication 5q35.2-q35.3 encompassing NSD1: is it really a reversed Sotos syndrome? Am. J. Med. Genet. A 161A, 2158–2166 (2013).
Sachwitz, J. et al. NSD1 duplication in Silver–Russell syndrome (SRS): molecular karyotyping in patients with SRS features: NSD1 duplication in SRS. Clin. Genet. 91, 73–78 (2016).
Peeters, S. et al. DNA methylation profiling and genomic analysis in 20 children with short stature who were born small-for-gestational age. J. Clin. Endocrinol. Metab. 105, e4730–e4741 (2020).
Brennan, K. et al. NSD1 inactivation defines an immune cold, DNA hypomethylated subtype in squamous cell carcinoma. Sci. Rep. 7, 17064 (2017).
Papillon-Cavanagh, S. et al. Impaired H3K36 methylation defines a subset of head and neck squamous cell carcinomas. Nat. Genet 49, 180–185 (2017). This study reveals that NSD1 and H3K36M mutations show a similar DNAme signature in head and neck squamous cell carcinomas.
Farhangdoost, N. et al. Chromatin dysregulation associated with NSD1 mutation in head and neck squamous cell carcinoma. Cell Rep. 34, 108769 (2021).
Creighton, C. J. et al. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499, 43–49 (2013).
Fang, D. et al. The histone H3.3K36M mutation reprograms the epigenome of chondroblastomas. Science 352, 1344–1348 (2016).
Lu, C. et al. Histone H3K36 mutations promote sarcomagenesis through altered histone methylation landscape. Science 352, 844–849 (2016).
Russler-Germain, D. A. et al. The R882H DNMT3A mutation associated with AML dominantly inhibits wild-type DNMT3A by blocking its ability to form active tetramers. Cancer Cell 25, 442–454 (2014).
Cancer Genome Atlas Research Network. The Cancer Genome Atlas pan-cancer analysis project. Nat. Genet. 45, 1113–1120 (2013).
Lu, R. et al. A model system for studying the DNMT3A hotspot mutation (DNMT3AR882) demonstrates a causal relationship between its dominant-negative effect and leukemogenesis. Cancer Res. 79, 3583–3594 (2019).
Spencer, D. H. et al. CpG Island hypermethylation mediated by DNMT3A Is a consequence of AML progression. Cell 168, 801–816 (2017).
Schwartz, Y. B. & Pirrotta, V. Polycomb silencing mechanisms and the management of genomic programmes. Nat. Rev. Genet. 8, 9–22 (2007).
Riising, E. M. et al. Gene silencing triggers polycomb repressive complex 2 recruitment to CpG Islands genome wide. Mol. Cell 55, 347–360 (2014).
Blackledge, N. P., Rose, N. R. & Klose, R. J. Targeting Polycomb systems to regulate gene expression: modifications to a complex story. Nat. Rev. Mol. Cell Biol. 16, 643–649 (2015).
Mierlo, G., van, Veenstra, G. J. C., Vermeulen, M. & Marks, H. The complexity of PRC2 subcomplexes. Trends Cell Biol. 29, 660–671 (2019).
Lindroth, A. M. et al. Antagonism between DNA and H3K27 methylation at the imprinted Rasgrf1 locus. PLoS Genet. 4, e1000145 (2008).
Wu, H. et al. Dnmt3a-dependent nonpromoter DNA methylation facilitates transcription of neurogenic genes. Science 329, 444–448 (2010).
Jermann, P., Hoerner, L., Burger, L. & Schübeler, D. Short sequences can efficiently recruit histone H3 lysine 27 trimethylation in the absence of enhancer activity and DNA methylation. Proc. Natl Acad. Sci. USA 111, E3415–E3421 (2014).
Li, H. et al. Polycomb-like proteins link the PRC2 complex to CpG islands. Nature 549, 287–291 (2017).
Perino, M. et al. MTF2 recruits polycomb repressive complex 2 by helical-shape-selective DNA binding. Nat. Genet. 50, 1002–1010 (2018).
Cooper, S. et al. Targeting polycomb to pericentric heterochromatin in embryonic stem cells reveals a Role for H2AK119u1 in PRC2 recruitment. Cell Rep. 7, 1456–1470 (2014).
Blackledge, N. P. et al. Variant PRC1 complex-dependent H2A ubiquitylation drives PRC2 recruitment and polycomb domain formation. Cell 157, 1445–1459 (2014).
Farcas, A. M. et al. KDM2B links the polycomb repressive complex 1 (PRC1) to recognition of CpG islands. eLife 1, e00205 (2012).
Brinkman, A. B. et al. Sequential ChIP-bisulfite sequencing enables direct genome-scale investigation of chromatin and DNA methylation cross-talk. Genome Res. 22, 1128–1138 (2012). Using sequential ChIP-bisulfite sequencing, this study shows that H3K27me3 and DNAme are mutually exclusive at CGIs. In addition, it reveals altered H3K27me3 levels in Dnmt triple-knockout mESCs, indicating an antagonistic relationship between H3K27me3 and DNAme.
Reddington, J. P. et al. Redistribution of H3K27me3 upon DNA hypomethylation results in de-repression of Polycomb target genes. Genome Biol. 14, R25 (2013).
King, A. D. et al. Reversible regulation of promoter and enhancer histone landscape by DNA methylation in mouse embryonic stem cells. Cell Rep. 17, 289–302 (2016).
Manzo, M. et al. Isoform-specific localization of DNMT3A regulates DNA methylation fidelity at bivalent CpG islands. EMBO J. 36, 3421–3434 (2017).
McLaughlin, K. et al. DNA methylation directs polycomb-dependent 3D genome re-organization in naive pluripotency. Cell Rep. 29, 1974–1985 (2019).
Zhang, Y. et al. Targets and genomic constraints of ectopic Dnmt3b expression. eLife 7, e40757 (2018).
Murphy, P. J. et al. Single-molecule analysis of combinatorial epigenomic states in normal and tumor cells. Proc. Natl Acad. Sci. USA 110, 7772–7777 (2013).
Landan, G. et al. Epigenetic polymorphism and the stochastic formation of differentially methylated regions in normal and cancerous tissues. Nat. Genet. 44, 1207–1214 (2012).
Statham, A. L. et al. Bisulfite sequencing of chromatin immunoprecipitated DNA (BisChIP-seq) directly informs methylation status of histone-modified DNA. Genome Res. 22, 1120–1127 (2012).
Wu, H. et al. Dual functions of Tet1 in transcriptional regulation in mouse embryonic stem cells. Nature 473, 389–393 (2011).
Gu, T. et al. DNMT3A and TET1 cooperate to regulate promoter epigenetic landscapes in mouse embryonic stem cells. Genome Biol. 19, 88 (2018).
Gibson, W. T. et al. Mutations in EZH2 cause Weaver syndrome. Am. J. Hum. Genet. 90, 110–118 (2011).
Cohen, A. S. A. et al. A novel mutation in EED associated with overgrowth. J. Hum. Genet. 60, 339–342 (2015).
Imagawa, E. et al. Novel SUZ12 mutations in Weaver-like syndrome. Clin. Genet. 94, 461–466 (2018).
Imagawa, E. et al. Mutations in genes encoding polycomb repressive complex 2 subunits cause Weaver syndrome. Hum. Mutat. 38, 637–648 (2017).
Cohen, A. S. A. et al. Weaver syndrome-associated EZH2 protein variants show impaired histone methyltransferase function in vitro. Hum. Mutat. 37, 301–307 (2016).
Lee, C.-H. et al. Allosteric activation dictates PRC2 activity independent of its recruitment to chromatin. Mol. Cell 70, 422–434 (2018).
Lui, J. C. et al. Ezh2 mutations found in the Weaver overgrowth syndrome cause a partial loss of H3K27 histone methyltransferase activity. J. Clin. Endocrinol. Metab. 103, 1470–1478 (2018).
Choufani, S. et al. DNA methylation signature for EZH2 functionally classifies sequence variants in three PRC2 complex genes. Am. J. Hum. Genet. 106, 596–610 (2020).
Laugesen, A., Højfeldt, J. W. & Helin, K. Role of the Polycomb repressive complex 2 (PRC2) in transcriptional regulation and cancer. Cold Spring Harb. Perspect. Med. 6, a026575 (2016).
Varambally, S. et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419, 624–629 (2002).
Kleer, C. G. et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc. Natl Acad. Sci. USA 100, 11606–11611 (2003).
Ueda, T. et al. EED mutants impair polycomb repressive complex 2 in myelodysplastic syndrome and related neoplasms. Leukemia 26, 2557–2560 (2012).
Lee, W. et al. PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors. Nat. Genet. 46, 1227–1232 (2014).
Wojcik, J. B. et al. Epigenomic reordering induced by polycomb loss drives oncogenesis but leads to therapeutic vulnerabilities in malignant peripheral nerve sheath tumors. Cancer Res. 79, 3205–3219 (2019).
Gal-Yam, E. N. et al. Frequent switching of Polycomb repressive marks and DNA hypermethylation in the PC3 prostate cancer cell line. Proc. Natl Acad. Sci. USA 105, 12979–12984 (2008).
Reddington, J. P., Sproul, D. & Meehan, R. R. DNA methylation reprogramming in cancer: does it act by re-configuring the binding landscape of Polycomb repressive complexes? Bioessays 36, 134–140 (2013).
Schwartzentruber, J. et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482, 226–231 (2012).
Wu, G. et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat. Genet. 44, 251–253 (2012).
Bender, S. et al. Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas. Cancer Cell 24, 660–672 (2013).
Chan, K.-M. et al. The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression. Genes Dev. 27, 985–990 (2013).
Harutyunyan, A. S. et al. H3K27M induces defective chromatin spread of PRC2-mediated repressive H3K27me2/me3 and is essential for glioma tumorigenesis. Nat. Commun. 10, 1262 (2019).
Streubel, G. et al. The H3K36me2 methyltransferase Nsd1 demarcates PRC2-mediated H3K27me2 and H3K27me3 domains in embryonic stem cells. Mol. Cell 70, 371–379 (2018). This study shows that loss of NSD1-mediated H3K36me2 leads to expansion of H3K27me3 domains and is among the first studies to indicate antagonistic interplay between H3K36me2 and H3K27me3.
Xiao, S. et al. Comparative epigenomic annotation of regulatory DNA. Cell 149, 1381–1392 (2012).
Yuan, W. et al. H3K36 methylation antagonizes PRC2-mediated H3K27 methylation. J. Biol. Chem. 286, 7983–7989 (2011). This study reveals that H3K27me3 and H3K36me2/me3 rarely co-exist on the same histone tail and that PRC2 activity is inhibited by H3K36 methylation.
Zheng, Y. et al. Total kinetic analysis reveals how combinatorial methylation patterns are established on lysines 27 and 36 of histone H3. Proc. Natl Acad. Sci. USA 109, 13549–13554 (2012).
Voigt, P. et al. Asymmetrically modified nucleosomes. Cell 151, 181–193 (2012).
Schmitges, F. W. et al. Histone methylation by PRC2 is inhibited by active chromatin marks. Mol. Cell 42, 330–341 (2011).
Jani, K. S. et al. Histone H3 tail binds a unique sensing pocket in EZH2 to activate the PRC2 methyltransferase. Proc. Natl Acad. Sci. USA 116, 8295–8300 (2019). This study demonstrates that EZH2 can sense the H3K36 methylation state, with unmodified H3K36 promoting PRC2 enzymatic activity towards H3K27.
Finogenova, K. et al. Structural basis for PRC2 decoding of active histone methylation marks H3K36me2/3. eLife 9, e61964 (2020).
Hosogane, M., Funayama, R., Shirota, M. & Nakayama, K. Lack of transcription triggers H3K27me3 accumulation in the gene body. Cell Rep. 16, 696–706 (2016).
Brumbaugh, J. et al. Inducible histone K-to-M mutations are dynamic tools to probe the physiological role of site-specific histone methylation in vitro and in vivo. Nat. Cell Biol. 21, 1449–1461 (2019).
Abe, S., Nagatomo, H., Sasaki, H. & Ishiuchi, T. A histone H3.3K36M mutation in mice causes an imbalance of histone modifications and defects in chondrocyte differentiation. Epigenetics https://doi.org/10.1080/15592294.2020.1841873 (2020).
Rajagopalan, K. N. et al. Depletion of H3K36me2 recapitulates epigenomic and phenotypic changes induced by the H3.3K36M oncohistone mutation. Proc. Natl Acad. Sci. USA 118, e2021795118 (2021).
Behjati, S. et al. Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone. Nat. Genet. 45, 1479–1482 (2013).
Zhang, Y. et al. Molecular basis for the role of oncogenic histone mutations in modulating H3K36 methylation. Sci. Rep. 7, 43906 (2017).
Shi, L., Shi, J., Shi, X., Li, W. & Wen, H. Histone H3.3 G34 mutations alter histone H3K36 and H3K27 methylation in cis. J. Mol. Biol. 430, 1562–1565 (2018).
Jain, S. U. et al. Histone H3.3 G34 mutations promote aberrant PRC2 activity and drive tumor progression. Proc. Natl Acad. Sci. USA 117, 27354–27364 (2020).
Sankaran, S. M. & Gozani, O. Characterization of H3.3K36M as a tool to study H3K36 methylation in cancer cells. Epigenetics 12, 917–922 (2017).
Oksuz, O. et al. Capturing the onset of PRC2-mediated repressive domain formation. Mol. Cell 70, 1149–1162 (2018).
Stafford, J. M. et al. Multiple modes of PRC2 inhibition elicit global chromatin alterations in H3K27M pediatric glioma. Sci. Adv. 4, eaau5935 (2018). This study shows that the loss of H3K27me3 observed in diffuse intrinsic pontine gliomas that harbour the H3K27M mutation is accompanied by a gain in H3K36me2.
Harutyunyan, A. S. et al. H3K27M in gliomas causes a one-step decrease in H3K27 methylation and reduced spreading within the constraints of H3K36 methylation. Cell Rep. 33, 108390 (2020).
Deshmukh, S., Ptack, A., Krug, B. & Jabado, N. Oncohistones: a roadmap to stalled development. FEBS J. https://doi.org/10.1111/febs.15963 (2021).
Weinberg, D. N. et al. Two competing mechanisms of DNMT3A recruitment regulate the dynamics of de novo DNA methylation at PRC1-targeted CpG islands. Nat. Genet 53, 794–800 (2021).
Kato, Y. et al. Role of the Dnmt3 family in de novo methylation of imprinted and repetitive sequences during male germ cell development in the mouse. Hum. Mol. Genet. 16, 2272–2280 (2007).
Dobrinić, P., Szczurek, A. T. & Klose, R. J. PRC1 drives Polycomb-mediated gene repression by controlling transcription initiation and burst frequency. Preprint at bioRxiv https://www.biorxiv.org/content/10.1101/2020.10.09.333294v1 (2020).
Strom, A. R. et al. HP1α is a chromatin crosslinker that controls nuclear and mitotic chromosome mechanics. eLife 10, e63972 (2021).
Lewis, P. W. et al. Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science 340, 857–861 (2013).
Yan, Q., Cho, E., Lockett, S. & Muegge, K. Association of Lsh, a regulator of DNA methylation, with pericentromeric heterochromatin is dependent on intact heterochromatin. Mol. Cell Biol. 23, 8416–8428 (2003).
Culver-Cochran, A. E. & Chadwick, B. P. Loss of WSTF results in spontaneous fluctuations of heterochromatin formation and resolution, combined with substantial changes to gene expression. BMC Genomics 14, 740 (2013).
Acknowledgements
The authors thank A. Bogutz, T. Baubec and J. Majewski for critical reading of the manuscript. This work was supported by CIHR grants PJT-153049 and PJT-166170. The authors apologize to the many colleagues who have made significant contributions to the field but whose work could not be cited or discussed owing to space limitations.
Author information
Authors and Affiliations
Contributions
The authors contributed equally to all aspects of the article.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Peer review information
Nature Reviews Genetics thanks Scott Rothbart, Duncan Sproul, Francesca Taglini and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Glossary
- DNA methyltransferases
-
(DNMTs). A family of enzymes that deposit a methyl group on cytosine DNA nucleotides, mainly in the context of cytosine–guanine dinucleotides.
- Transposable elements
-
(TEs). Also known as ‘jumping genes’, DNA sequences that can insert in new positions in the genome. The vast majority of TEs in the genome are no longer mobile, as they have accumulated mutations over evolutionary time.
- CpG islands
-
(CGIs). Regions in the genome with high GC content that are enriched for CpG dinucleotides.
- Imprinted gametic differentially methylated regions
-
(gDMRs). Regions marked by parent of origin-specific DNA methylation on one of the two parental alleles in the offspring, resulting in monoallelic gene expression. Imprints are established in the parental germ line and maintained after fertilization.
- Inner cell mass
-
(ICM). Pluripotent cells residing in the blastocyst, which can be isolated and cultured in vitro as embryonic stem cells.
- Dnmt triple-knockout mESCs
-
Mouse embryonic stem cells (mESCs) that lack de novo and maintenance DNA methylation owing to genetic deletions of the DNA methyltransferase genes Dnmt3a, Dnmt3b and Dnmt1.
- Epiblast
-
The pluripotent primary lineage that arises from the inner cell mass of the blastocyst.
- Bivalent
-
The dual presence of histone H3 lysine 4 trimethylation (H3K4me3) and H3K27me3, mainly found in the promoter regions of developmentally important transcription factors.
- Retrotransposons
-
A class of transposable elements that are transcribed into mRNA and then reverse transcribed into DNA before integrating in the genome.
- Krüppel-associated box domain zinc-finger proteins
-
(KRAB-ZFPs). The largest family of ZFP-based transcription factors in mouse and human genomes.
- 2i medium
-
Medium supplemented with leukaemia inhibitory factor and two small-molecule kinase inhibitors (of MEK and GSK3) to establish mouse embryonic stem cells (mESCs) in a naive-like ground state that is characterized by global DNA hypomethylation.
- Epiblast-like cells
-
An in vitro model of epiblast cells. They are derived by culturing mouse embryonic stem cells (mESCs) in the presence of activin A and basic fibroblast growth factor and are characterized by global DNA hypermethylation.
- PGC-like cells
-
An in vitro model of primordial germ cells (PGCs). They are derived by culturing epiblast-like cells in the presence of bone morphogenetic protein, leukaemia inhibitory factor, stem cell factor and epidermal growth factor. They are characterized by global DNA hypomethylation.
- DNMT3C
-
DNA methyltransferase 3C (DNMT3C) is a recently discovered rodent-specific DNMT3 paralogue that is responsible for de novo DNA methylation of evolutionarily young retrotransposons in male germ cells.
- Prospermatogonia
-
(PSG). Quiescent prenatal male germ cells derived from primordial germ cells.
- Hutchinson–Gilford progeria syndrome
-
(HGPS). A premature ageing syndrome caused by a de novo heterozygous mutation in the lamin A (LMNA) gene.
- Heterochromatin protein 1
-
(HP1). A family of three HP1 paralogues (HP1α, HP1β and HP1γ, encoded by CBX5, CBX1 and CBX3 genes, respectively) that can bind to H3K9me2/me3 and are involved in heterochromatin formation and gene silencing.
- Partially methylated domains
-
(PMDs). Large undermethylated, genomic regions localized in heterochromatic/lamina-associated domains. PMDs are generally gene poor and characterized by late replication timing, H3K9me3 enrichment and low CpG density.
- Oncohistone
-
Cancer-associated mutations in histone genes, including H3.1 and H3.3 genes, that affect residues in the histone tail near or overlapping with residues that harbour post-translational modifications in wild-type histones.
- DNA methylation valleys
-
(DMVs). Large genomic regions with low levels of DNA methylation. Also called DNA methylation canyons.
Rights and permissions
About this article
Cite this article
Janssen, S.M., Lorincz, M.C. Interplay between chromatin marks in development and disease. Nat Rev Genet 23, 137–153 (2022). https://doi.org/10.1038/s41576-021-00416-x
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41576-021-00416-x
This article is cited by
-
Frequency, morbidity and equity — the case for increased research on male fertility
Nature Reviews Urology (2024)
-
Non-canonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cells
Nature Communications (2024)
-
Regulation and clinical potential of telomerase reverse transcriptase (TERT/hTERT) in breast cancer
Cell Communication and Signaling (2023)
-
Characterization of H3K9me3 and DNA methylation co-marked CpG-rich regions during mouse development
BMC Genomics (2023)
-
A quantum physics layer of epigenetics: a hypothesis deduced from charge transfer and chirality-induced spin selectivity of DNA
Clinical Epigenetics (2023)
