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Review article: Biomedical intelligence

Vol. 150 No. 3536 (2020)

DNA methyltransferases hitchhiking on chromatin

  • Ino D. Karemaker
  • Tuncay Baubec
Cite this as:
Swiss Med Wkly. 2020;150:w20329
Published
24.08.2020

Summary

DNA methylation is an epigenetic modification that plays a central regulatory role in various biological processes. Methyl groups are coupled to cytosines by the family of DNA methyltransferases (DNMTs), where DNMT1 is the main maintenance enzyme and the DNMT3 branch of the family is mostly responsible for de novo methylation. The regulation and function of DNA methylation are dependent on the genomic and chromatin context, such as binding sites for transcription factors or the presence of histone marks. Yet how local context, especially chromatin marks, influences the recruitment of the different DNMTs to their genomic target sites remains to be completely revealed. Elucidating the crosstalk between different histone modifications and DNA methylation, and their combined effect on the genome-wide epigenetic landscape, is of particular interest. Aberrant distribution of chromatin marks that guide DNMT activity or DNMT mutations that influence their correct recruitment to the genome have a profound impact on the deposition of DNA methylation, with consequences for genome function and gene activity. In this review, we describe the current state of knowledge on this topic and provide an overview on how chromatin marks can guide DNMT recruitment in healthy and diseased cells.

References

  1. Culp LA, Dore E, Brown GM. Methylated bases in DNA of animal origin. Arch Biochem Biophys. 1970;136(1):73–9. doi:.https://doi.org/10.1016/0003-9861(70)90328-0
  2. Lister R, Pelizzola M, Dowen RH, Hawkins RD, Hon G, Tonti-Filippini J, et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature. 2009;462(7271):315–22. doi:.https://doi.org/10.1038/nature08514
  3. Bird A. The dinucleotide CG as a genomic signalling module. J Mol Biol. 2011;409(1):47–53. doi:.https://doi.org/10.1016/j.jmb.2011.01.056
  4. Bird AP. CpG-rich islands and the function of DNA methylation. Nature. 1986;321(6067):209–13. doi:.https://doi.org/10.1038/321209a0
  5. Mohandas T, Sparkes RS, Shapiro LJ. Reactivation of an inactive human X chromosome: evidence for X inactivation by DNA methylation. Science. 1981;211(4480):393–6. doi:.https://doi.org/10.1126/science.6164095
  6. Li E, Beard C, Jaenisch R. Role for DNA methylation in genomic imprinting. Nature. 1993;366(6453):362–5. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8247133. doi:.https://doi.org/10.1038/366362a0
  7. Borgel J, Guibert S, Li Y, Chiba H, Schübeler D, Sasaki H, et al. Targets and dynamics of promoter DNA methylation during early mouse development. Nat Genet. 2010;42(12):1093–100. doi:.https://doi.org/10.1038/ng.708
  8. Walsh CP, Chaillet JR, Bestor TH. Transcription of IAP endogenous retroviruses is constrained by cytosine methylation. Nat Genet. 1998;20(2):116–7. doi:.https://doi.org/10.1038/2413
  9. Barau J, Teissandier A, Zamudio N, Roy S, Nalesso V, Hérault Y, et al. The DNA methyltransferase DNMT3C protects male germ cells from transposon activity. Science. 2016;354(6314):909–12. doi:.https://doi.org/10.1126/science.aah5143
  10. Hata K, Okano M, Lei H, Li E. Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice. Development. 2002;129(8):1983–93.
  11. Goll MG, Bestor TH. Eukaryotic cytosine methyltransferases. Annu Rev Biochem. 2005;74(1):481–514. doi:.https://doi.org/10.1146/annurev.biochem.74.010904.153721
  12. Kriaucionis S, Heintz N. The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science. 2009;324(5929):929–30. doi:.https://doi.org/10.1126/science.1169786
  13. Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009;324(5929):930–5. doi:.https://doi.org/10.1126/science.1170116
  14. Ginno PA, Gaidatzis D, Feldmann A, Hoerner L, Imanci D, Burger L, et al. A genome-scale map of DNA methylation turnover identifies site-specific dependencies of DNMT and TET activity. Nat Commun. 2020;11(1):2680. doi:.https://doi.org/10.1038/s41467-020-16354-x
  15. Charlton J, Jung EJ, Mattei AL, Bailly N, Liao J, Martin EJ, et al. TETs compete with DNMT3 activity in pluripotent cells at thousands of methylated somatic enhancers. Nat Genet. 2020;52(8):819–27. doi:.https://doi.org/10.1038/s41588-020-0639-9
  16. Ambrosi C, Manzo M, Baubec T. Dynamics and Context-Dependent Roles of DNA Methylation. J Mol Biol. 2017;429(10):1459–75. doi:.https://doi.org/10.1016/j.jmb.2017.02.008
  17. Kouzarides T. Chromatin modifications and their function. Cell. 2007;128(4):693–705. doi:.https://doi.org/10.1016/j.cell.2007.02.005
  18. Cedar H, Bergman Y. Linking DNA methylation and histone modification: patterns and paradigms. Nat Rev Genet. 2009;10(5):295–304. doi:.https://doi.org/10.1038/nrg2540
  19. Bestor T, Laudano A, Mattaliano R, Ingram V. Cloning and sequencing of a cDNA encoding DNA methyltransferase of mouse cells. The carboxyl-terminal domain of the mammalian enzymes is related to bacterial restriction methyltransferases. J Mol Biol. 1988;203(4):971–83. doi:.https://doi.org/10.1016/0022-2836(88)90122-2
  20. Takeshita K, Suetake I, Yamashita E, Suga M, Narita H, Nakagawa A, et al. Structural insight into maintenance methylation by mouse DNA methyltransferase 1 (Dnmt1). Proc Natl Acad Sci USA. 2011;108(22):9055–9. doi:.https://doi.org/10.1073/pnas.1019629108
  21. Rountree MR, Bachman KE, Baylin SB. DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. Nat Genet. 2000;25(3):269–77. doi:.https://doi.org/10.1038/77023
  22. Gruenbaum Y, Cedar H, Razin A. Substrate and sequence specificity of a eukaryotic DNA methylase. Nature. 1982;295(5850):620–2. doi:.https://doi.org/10.1038/295620a0
  23. Yoder JA, Soman NS, Verdine GL, Bestor TH. DNA (cytosine-5)-methyltransferases in mouse cells and tissues. Studies with a mechanism-based probe. J Mol Biol. 1997;270(3):385–95. doi:.https://doi.org/10.1006/jmbi.1997.1125
  24. Arand J, Spieler D, Karius T, Branco MR, Meilinger D, Meissner A, et al. In vivo control of CpG and non-CpG DNA methylation by DNA methyltransferases. PLoS Genet. 2012;8(6):e1002750. doi:.https://doi.org/10.1371/journal.pgen.1002750
  25. Dodge JE, Okano M, Dick F, Tsujimoto N, Chen T, Wang S, et al. Inactivation of Dnmt3b in mouse embryonic fibroblasts results in DNA hypomethylation, chromosomal instability, and spontaneous immortalization. J Biol Chem. 2005;280(18):17986–91. doi:.https://doi.org/10.1074/jbc.M413246200
  26. Feng J, Zhou Y, Campbell SL, Le T, Li E, Sweatt JD, et al. Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons. Nat Neurosci. 2010;13(4):423–30. doi:.https://doi.org/10.1038/nn.2514
  27. Jeltsch A, Jurkowska RZ. New concepts in DNA methylation. Trends Biochem Sci. 2014;39(7):310–8. doi:.https://doi.org/10.1016/j.tibs.2014.05.002
  28. Dahlet T, Argüeso Lleida A, Al Adhami H, Dumas M, Bender A, Ngondo RP, et al. Genome-wide analysis in the mouse embryo reveals the importance of DNA methylation for transcription integrity. Nat Commun. 2020;11(1):3153. doi:.https://doi.org/10.1038/s41467-020-16919-w
  29. Chuang LSH, Ian HI, Koh TW, Ng HH, Xu G, Li BFL. Human DNA-(cytosine-5) methyltransferase-PCNA complex as a target for p21WAF1. Science. 1997;277(5334):1996–2000. doi:.https://doi.org/10.1126/science.277.5334.1996
  30. Spada F, Haemmer A, Kuch D, Rothbauer U, Schermelleh L, Kremmer E, et al. DNMT1 but not its interaction with the replication machinery is required for maintenance of DNA methylation in human cells. J Cell Biol. 2007;176(5):565–71. doi:.https://doi.org/10.1083/jcb.200610062
  31. Sharif J, Muto M, Takebayashi S, Suetake I, Iwamatsu A, Endo TA, et al. The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA. Nature. 2007;450(7171):908–12. doi:.https://doi.org/10.1038/nature06397
  32. 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. 2008;455(7214):818–21. doi:.https://doi.org/10.1038/nature07249
  33. Li T, Wang L, Du Y, Xie S, Yang X, Lian F, et al. Structural and mechanistic insights into UHRF1-mediated DNMT1 activation in the maintenance DNA methylation. Nucleic Acids Res. 2018;46(6):3218–31. doi:.https://doi.org/10.1093/nar/gky104
  34. 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. 2008;28(2):705–17. doi:.https://doi.org/10.1128/MCB.01598-07
  35. Nady N, Lemak A, Walker JR, Avvakumov GV, Kareta MS, Achour M, et al. Recognition of multivalent histone states associated with heterochromatin by UHRF1 protein. J Biol Chem. 2011;286(27):24300–11. doi:.https://doi.org/10.1074/jbc.M111.234104
  36. Rajakumara E, Wang Z, Ma H, Hu L, Chen H, Lin Y, et al. PHD finger recognition of unmodified histone H3R2 links UHRF1 to regulation of euchromatic gene expression. Mol Cell. 2011;43(2):275–84. doi:.https://doi.org/10.1016/j.molcel.2011.07.006
  37. Ren W, Fan H, Grimm SA, Guo Y, Kim JJ, Li L, et al. Direct readout of heterochromatic H3K9me3 regulates DNMT1-mediated maintenance DNA methylation. bioRxiv. 2020;2020:04.27.064493. https://www.biorxiv.org/content/10.1101/2020.04.27.064493v1.full.
  38. Ishiyama S, Nishiyama A, Saeki Y, Moritsugu K, Morimoto D, Yamaguchi L, 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. 2017;68(2):350–360.e7. doi:.https://doi.org/10.1016/j.molcel.2017.09.037
  39. Nishiyama A, Mulholland CB, Bultmann S, Kori S, Endo A, Saeki Y, et al. Two distinct modes of DNMT1 recruitment ensure stable maintenance DNA methylation. Nat Commun. 2020;11(1):1222. doi:.https://doi.org/10.1038/s41467-020-15006-4
  40. Molaro A, Malik HS, Bourc’his D. Dynamic evolution of de novo DNA methyltransferases in rodent and primate genomes. Mol Biol Evol. 2020;37(7):1882–92. doi:.https://doi.org/10.1093/molbev/msaa044
  41. Aapola U, Shibuya K, Scott HS, Ollila J, Vihinen M, Heino M, et al. Isolation and initial characterization of a novel zinc finger gene, DNMT3L, on 21q22.3, related to the cytosine-5-methyltransferase 3 gene family. Genomics. 2000;65(3):293–8. doi:.https://doi.org/10.1006/geno.2000.6168
  42. Bourc’his D, Xu GL, Lin CS, Bollman B, Bestor TH. Dnmt3L and the establishment of maternal genomic imprints. Science. 2001;294(5551):2536–9. doi:.https://doi.org/10.1126/science.1065848
  43. Suetake I, Shinozaki F, Miyagawa J, Takeshima H, Tajima S. DNMT3L stimulates the DNA methylation activity of Dnmt3a and Dnmt3b through a direct interaction. J Biol Chem. 2004;279(26):27816–23. doi:.https://doi.org/10.1074/jbc.M400181200
  44. Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell. 1999;99(3):247–57. doi:.https://doi.org/10.1016/S0092-8674(00)81656-6
  45. Okano M, Xie S, Li E. Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nat Genet. 1998;19(3):219–20. doi:.https://doi.org/10.1038/890
  46. Zhang ZM, Lu R, Wang P, Yu Y, Chen D, Gao L, et al. Structural basis for DNMT3A-mediated de novo DNA methylation. Nature. 2018;554(7692):387–91. doi:.https://doi.org/10.1038/nature25477
  47. Lin C-C, Chen Y-P, Yang W-Z, Shen JCK, Yuan HS. Structural insights into CpG-specific DNA methylation by human DNA methyltransferase 3B. Nucleic Acids Res. 2020;48(7):3949–61. doi:.https://doi.org/10.1093/nar/gkaa111
  48. Gao L, Emperle M, Guo Y, Grimm SA, Ren W, Adam S, et al. Comprehensive structure-function characterization of DNMT3B and DNMT3A reveals distinctive de novo DNA methylation mechanisms. Nat Commun. 2020;11(1):3355. doi:.https://doi.org/10.1038/s41467-020-17109-4
  49. Anteneh H, Fang J, Song J. Structural basis for impairment of DNA methylation by the DNMT3A R882H mutation. Nat Commun. 2020;11(1):2294. doi:.https://doi.org/10.1038/s41467-020-16213-9
  50. Ooi SKT, Qiu C, Bernstein E, Li K, Jia D, Yang Z, et al. DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature. 2007;448(7154):714–7. doi:.https://doi.org/10.1038/nature05987
  51. Otani J, Nankumo T, Arita K, Inamoto S, Ariyoshi M, Shirakawa M. Structural basis for recognition of H3K4 methylation status by the DNA methyltransferase 3A ATRX-DNMT3-DNMT3L domain. EMBO Rep. 2009;10(11):1235–41. doi:.https://doi.org/10.1038/embor.2009.218
  52. Zhang Y, Jurkowska R, Soeroes S, Rajavelu A, Dhayalan A, Bock I, 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. 2010;38(13):4246–53. doi:.https://doi.org/10.1093/nar/gkq147
  53. Noh KM, Wang H, Kim HR, Wenderski W, Fang F, Li CH, et al. Engineering of a Histone-Recognition Domain in Dnmt3a Alters the Epigenetic Landscape and Phenotypic Features of Mouse ESCs. Mol Cell. 2015;59(1):89–103. doi:.https://doi.org/10.1016/j.molcel.2015.05.017
  54. Okitsu CY, Hsieh C-L. DNA methylation dictates histone H3K4 methylation. Mol Cell Biol. 2007;27(7):2746–57. doi:.https://doi.org/10.1128/MCB.02291-06
  55. Weber M, Hellmann I, Stadler MB, Ramos L, Pääbo S, Rebhan M, et al. Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nat Genet. 2007;39(4):457–66. doi:.https://doi.org/10.1038/ng1990
  56. Guo X, Wang L, Li J, Ding Z, Xiao J, Yin X, et al. Structural insight into autoinhibition and histone H3-induced activation of DNMT3A. Nature. 2015;517(7536):640–4. doi:.https://doi.org/10.1038/nature13899
  57. Dhayalan A, Rajavelu A, Rathert P, Tamas R, Jurkowska RZ, Ragozin S, et al. The Dnmt3a PWWP domain reads histone 3 lysine 36 trimethylation and guides DNA methylation. J Biol Chem. 2010;285(34):26114–20. doi:.https://doi.org/10.1074/jbc.M109.089433
  58. Weinberg DN, Papillon-Cavanagh S, Chen H, Yue Y, Chen X, Rajagopalan KN, et al. The histone mark H3K36me2 recruits DNMT3A and shapes the intergenic DNA methylation landscape. Nature. 2019;573(7773):281–6. doi:.https://doi.org/10.1038/s41586-019-1534-3
  59. Baubec T, Colombo DF, Wirbelauer C, Schmidt J, Burger L, Krebs AR, et al. Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation. Nature. 2015;520(7546):243–7. doi:.https://doi.org/10.1038/nature14176
  60. Manzo M, Wirz J, Ambrosi C, Villaseñor R, Roschitzki B, Baubec T. Isoform-specific localization of DNMT3A regulates DNA methylation fidelity at bivalent CpG islands. EMBO J. 2017;36(23):3421–34. doi:.https://doi.org/10.15252/embj.201797038
  61. Gu T, Lin X, Cullen SM, Luo M, Jeong M, Estecio M, et al. DNMT3A and TET1 cooperate to regulate promoter epigenetic landscapes in mouse embryonic stem cells. Genome Biol. 2018;19(1):88. doi:.https://doi.org/10.1186/s13059-018-1464-7
  62. Brinkman AB, Gu H, Bartels SJJ, Zhang Y, Matarese F, Simmer F, et al. Sequential ChIP-bisulfite sequencing enables direct genome-scale investigation of chromatin and DNA methylation cross-talk. Genome Res. 2012;22(6):1128–38. doi:.https://doi.org/10.1101/gr.133728.111
  63. Epsztejn-Litman S, Feldman N, Abu-Remaileh M, Shufaro Y, Gerson A, Ueda J, et al. De novo DNA methylation promoted by G9a prevents reprogramming of embryonically silenced genes. Nat Struct Mol Biol. 2008;15(11):1176–83. doi:.https://doi.org/10.1038/nsmb.1476
  64. Viré E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C, et al. The Polycomb group protein EZH2 directly controls DNA methylation. Nature. 2006;439(7078):871–4. doi:.https://doi.org/10.1038/nature04431
  65. Neri F, Krepelova A, Incarnato D, Maldotti M, Parlato C, Galvagni F, et al. Dnmt3L antagonizes DNA methylation at bivalent promoters and favors DNA methylation at gene bodies in ESCs. Cell. 2013;155(1):121–34. doi:.https://doi.org/10.1016/j.cell.2013.08.056
  66. Rush M, Appanah R, Lee S, Lam LL, Goyal P, Lorincz MC. Targeting of EZH2 to a defined genomic site is sufficient for recruitment of Dnmt3a but not de novo DNA methylation. Epigenetics. 2009;4(6):404–14. doi:.https://doi.org/10.4161/epi.4.6.9392
  67. Hagarman JA, Motley MP, Kristjansdottir K, Soloway PD. Coordinate regulation of DNA methylation and H3K27me3 in mouse embryonic stem cells. PLoS One. 2013;8(1):e53880. doi:.https://doi.org/10.1371/journal.pone.0053880
  68. Veland N, Lu Y, Hardikar S, Gaddis S, Zeng Y, Liu B, et al. DNMT3L facilitates DNA methylation partly by maintaining DNMT3A stability in mouse embryonic stem cells. Nucleic Acids Res. 2019;47(1):152–67. doi:.https://doi.org/10.1093/nar/gky947
  69. Fuks F, Hurd PJ, Deplus R, Kouzarides T. The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase. Nucleic Acids Res. 2003;31(9):2305–12. doi:.https://doi.org/10.1093/nar/gkg332
  70. Li H, Rauch T, Chen ZX, Szabó PE, Riggs AD, Pfeifer GP. The histone methyltransferase SETDB1 and the DNA methyltransferase DNMT3A interact directly and localize to promoters silenced in cancer cells. J Biol Chem. 2006;281(28):19489–500. doi:.https://doi.org/10.1074/jbc.M513249200
  71. Li E, Bestor TH, Jaenisch R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell. 1992;69(6):915–26. doi:.https://doi.org/10.1016/0092-8674(92)90611-F
  72. Klein CJ, Botuyan MV, Wu Y, Ward CJ, Nicholson GA, Hammans S, et al. Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss. Nat Genet. 2011;43(6):595–600. doi:.https://doi.org/10.1038/ng.830
  73. Winkelmann J, Lin L, Schormair B, Kornum BR, Faraco J, Plazzi G, et al. Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy. Hum Mol Genet. 2012;21(10):2205–10. doi:.https://doi.org/10.1093/hmg/dds035
  74. Yang L, Rau R, Goodell MA. DNMT3A in haematological malignancies. Nat Rev Cancer. 2015;15(3):152–65. doi:.https://doi.org/10.1038/nrc3895
  75. Roller A, Grossmann V, Bacher U, Poetzinger F, Weissmann S, Nadarajah N, et al. Landmark analysis of DNMT3A mutations in hematological malignancies. Leukemia. 2013;27(7):1573–8. doi:.https://doi.org/10.1038/leu.2013.65
  76. Buscarlet M, Provost S, Zada YF, Barhdadi A, Bourgoin V, Lépine G, et al. DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions. Blood. 2017;130(6):753–62. doi:.https://doi.org/10.1182/blood-2017-04-777029
  77. Jaiswal S, Libby P. Clonal haematopoiesis: connecting ageing and inflammation in cardiovascular disease. Nat Rev Cardiol. 2020;17(3):137–44. doi:.https://doi.org/10.1038/s41569-019-0247-5
  78. Tatton-Brown K, Seal S, Ruark E, Harmer J, Ramsay E, Del Vecchio Duarte S, et al.; Childhood Overgrowth Consortium. Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability. Nat Genet. 2014;46(4):385–8. doi:.https://doi.org/10.1038/ng.2917
  79. Heyn P, Logan CV, Fluteau A, Challis RC, Auchynnikava T, Martin CA, et al. Gain-of-function DNMT3A mutations cause microcephalic dwarfism and hypermethylation of Polycomb-regulated regions. Nat Genet. 2019;51(1):96–105. doi:.https://doi.org/10.1038/s41588-018-0274-x
  80. Sendžikaitė G, Hanna CW, Stewart-Morgan KR, Ivanova E, Kelsey G. A DNMT3A PWWP mutation leads to methylation of bivalent chromatin and growth retardation in mice. Nat Commun. 2019;10(1):1884. doi:.https://doi.org/10.1038/s41467-019-09713-w
  81. Remacha L, Currás-Freixes M, Torres-Ruiz R, Schiavi F, Torres-Pérez R, Calsina B, et al. Gain-of-function mutations in DNMT3A in patients with paraganglioma. Genet Med. 2018;20(12):1644–51. doi:.https://doi.org/10.1038/s41436-018-0003-y
  82. Rondelet G, Dal Maso T, Willems L, Wouters J. Structural basis for recognition of histone H3K36me3 nucleosome by human de novo DNA methyltransferases 3A and 3B. J Struct Biol. 2016;194(3):357–67. doi:.https://doi.org/10.1016/j.jsb.2016.03.013
  83. Xu GL, Bestor TH, Bourc’his D, Hsieh CL, Tommerup N, Bugge M, et al. Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature. 1999;402(6758):187–91. doi:.https://doi.org/10.1038/46052
  84. Shirohzu H, Kubota T, Kumazawa A, Sado T, Chijiwa T, Inagaki K, et al. Three novel DNMT3B mutations in Japanese patients with ICF syndrome. Am J Med Genet. 2002;112(1):31–7. doi:.https://doi.org/10.1002/ajmg.10658
  85. Kirmizis A, Santos-Rosa H, Penkett CJ, Singer MA, Vermeulen M, Mann M, et al. Arginine methylation at histone H3R2 controls deposition of H3K4 trimethylation. Nature. 2007;449(7164):928–32. doi:.https://doi.org/10.1038/nature06160
  86. Migliori V, Müller J, Phalke S, Low D, Bezzi M, Mok WC, et al. Symmetric dimethylation of H3R2 is a newly identified histone mark that supports euchromatin maintenance. Nat Struct Mol Biol. 2012;19(2):136–44. doi:.https://doi.org/10.1038/nsmb.2209
  87. Mikkelsen TS, Ku M, Jaffe DB, Issac B, Lieberman E, Giannoukos G, et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature. 2007;448(7153):553–60. doi:.https://doi.org/10.1038/nature06008
  88. Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, et al. High-resolution profiling of histone methylations in the human genome. Cell. 2007;129(4):823–37. doi:.https://doi.org/10.1016/j.cell.2007.05.009
  89. Reddington JP, Perricone SM, Nestor CE, Reichmann J, Youngson NA, Suzuki M, et al. Redistribution of H3K27me3 upon DNA hypomethylation results in de-repression of Polycomb target genes. Genome Biol. 2013;14(3):R25. doi:.https://doi.org/10.1186/gb-2013-14-3-r25
  90. Joshi O, Wang SY, Kuznetsova T, Atlasi Y, Peng T, Fabre PJ, et al. Dynamic Reorganization of Extremely Long-Range Promoter-Promoter Interactions between Two States of Pluripotency. Cell Stem Cell. 2015;17(6):748–57. doi:.https://doi.org/10.1016/j.stem.2015.11.010
  91. McLaughlin K, Flyamer IM, Thomson JP, Mjoseng HK, Shukla R, Williamson I, et al. DNA methylation directs polycomb-dependent 3D genome re- organization in naive pluripotency. Cell Rep. 2019;29(7):1974–1985.e6. doi:.https://doi.org/10.1016/j.celrep.2019.10.031
  92. Jeong M, Sun D, Luo M, Huang Y, Challen GA, Rodriguez B, et al. Large conserved domains of low DNA methylation maintained by Dnmt3a. Nat Genet. 2014;46(1):17–23. doi:.https://doi.org/10.1038/ng.2836
  93. Jeltsch A, Jurkowska RZ. Allosteric control of mammalian DNA methyltransferases - a new regulatory paradigm. Nucleic Acids Res. 2016;44(18):8556–75. doi:.https://doi.org/10.1093/nar/gkw723
  94. Kim GD, Ni J, Kelesoglu N, Roberts RJ, Pradhan S. Co-operation and communication between the human maintenance and de novo DNA (cytosine-5) methyltransferases. EMBO J. 2002;21(15):4183–95. doi:.https://doi.org/10.1093/emboj/cdf401
  95. Handa V, Jeltsch A. Profound flanking sequence preference of Dnmt3a and Dnmt3b mammalian DNA methyltransferases shape the human epigenome. J Mol Biol. 2005;348(5):1103–12. doi:.https://doi.org/10.1016/j.jmb.2005.02.044
  96. Wienholz BL, Kareta MS, Moarefi AH, Gordon CA, Ginno PA, Chédin F. DNMT3L modulates significant and distinct flanking sequence preference for DNA methylation by DNMT3A and DNMT3B in vivo. PLoS Genet. 2010;6(9):e1001106. doi:.https://doi.org/10.1371/journal.pgen.1001106