Skip to main content

The Molecular Basis of DNA Methylation

  • Chapter
  • First Online:
DNA and Histone Methylation as Cancer Targets

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

In mammals, cytosine in CpG sequences in genomic DNA is often methylated at the 5th position. DNA methylation acts as a regulator of gene expression, and is crucial for development, especially in higher eukaryotes. Three DNA (cytosine-5)-methyltransferases, Dnmt1, Dnmt3a, and Dnmt3b, have been identified. Dnmt3a and Dnmt3b are mainly responsible for establishing DNA methylation patterns in the genome. Factors interacting with Dnmt3a or Dnmt3b, histone modifications, and their timing of expression act as determinants for sites to be methylated. Once DNA methylation patterns are established, the patterns are maintained by Dnmt1, which favors methylation of hemi-methylated DNA (where only one DNA strand is methylated) after DNA replication and repair. For maintenance DNA methylation, interacting factors and histone modifications are also necessary in vivo. In this chapter, the function of DNA methylation and the molecular mechanisms to establish and maintain DNA methylation are described.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Alabert C, Bukowski-Wills J-C, Lee S-B, Kustatscher G, Nakamura K, de Lima Alves F, Menard P, Mejlvang J, Rappsilber J, Groth A (2014) Nascent chromatin capture proteomics determines chromatin dynamics during DNA replication and identifies unknown fork components. Nat Cell Biol 16:281–293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Aoki A, Suetake I, Miyagawa J, Fujio T, Chijiwa T, Sasaki H, Tajima S (2001) Enzymatic properties of de novo-type mouse DNA (cytosine-5) methyltransferases. Nucleic Acids Res 29:3506–3512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Arand J, Spieler D, Karius T, Branco MR, Meilinger D, Meissner A, Jenuwein T, Xu G, Leonhardt H, Wolf V et al (2012) In vivo control of CpG and non-CpG DNA methylation by DNA methyltransferases. PLoS Genet 8:1–11

    Article  CAS  Google Scholar 

  4. Argentaro A, Yang J-C, Chapman L, Kowalczyk MS, Gibbons RJ, Higgs DR, Neuhaus D, Rhodes D (2007) Structural consequences of disease-causing mutations in the ATRX-DNMT3-DNMT3L (ADD) domain of the chromatin-associated protein ATRX. Proc Natl Acad Sci U S A 104:11939–11944

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Arita K, Ariyoshi M, Tochio H, Nakamura Y, Shirakawa M (2008) Recognition of hemi-methylated DNA by the SRA protein UHRF1 by a base-flipping mechanism. Nature 455:818–821

    Article  CAS  PubMed  Google Scholar 

  6. Arita K, Isogai S, Oda T, Unoki M, Sugita K, Sekiyama N, Kuwata K, Hamamoto R, Tochio H, Sato M et al (2012) Recognition of modification status on a histone H3 tail by linked histone reader modules of the epigenetic regulator UHRF1. Proc Natl Acad Sci U S A 109:12950–12955

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Avvakumov GV, Walker JR, Xue S, Li Y, Duan S, Bronner C, Arrowsmith CH, Dhe-Paganon S (2008) Structural basis for recognition of hemi-methylated DNA by the SRA domain of human UHRF1. Nature 455:822–825

    Article  CAS  PubMed  Google Scholar 

  8. Bashtrykov P, Jankevicius G, Smarandache A, Jurkowska RZ, Ragozin S, Jeltsch A (2012) Specificity of dnmt1 for methylation of hemimethylated CpG sites resides in its catalytic domain. Chem Biol 19:572–578

    Article  CAS  PubMed  Google Scholar 

  9. Baubec T, Colombo DF, Wirbelauer C, Schmidt J, Burger L, Krebs AR, Akalin A, Schübeler D (2015) Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation. Nature 520:243–247

    Article  CAS  PubMed  Google Scholar 

  10. Bell AC, Felsenfeld G (2000) Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene. Nature 405:482–485

    Article  CAS  PubMed  Google Scholar 

  11. Bergman Y, Cedar H (2013) DNA methylation dynamics in health and disease. Nat Struct Mol Biol 20:274–281

    Article  CAS  PubMed  Google Scholar 

  12. Berkyurek AC, Suetake I, Arita K, Takeshita K, Nakagawa A, Shirakawa M, Tajima S (2014) The DNA methyltransferase Dnmt1 directly interacts with the SET and RING finger-associated (SRA) domain of the multifunctional protein Uhrf1 to facilitate accession of the catalytic center to hemi-methylated DNA. J Biol Chem 289:379–386

    Article  CAS  PubMed  Google Scholar 

  13. Bestor T, Laudano A, Mattaliano R, Ingram V (1988) Cloning and sequencing of a cDNA encoding DNA methyltransferase of mouse cells. J Mol Biol 203:971–983

    Article  CAS  PubMed  Google Scholar 

  14. Biniszkiewicz D, Gribnau J, Ramsahoye B, Gaudet F, Eggan K, Humpherys D, Mastrangelo M, Jun Z, Walter J, Jaenisch R (2002) Dnmt1 Overexpression Causes Genomic Hypermethylation, Loss of Imprinting, and Embryonic Lethality. Mol Cell Biol 22:2124–2135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bird A (2002) DNA methylation patterns and epigenetic memory DNA methylation patterns and epigenetic memory. Genes Dev 16:6–21

    Article  CAS  PubMed  Google Scholar 

  16. Booth MJ, Branco MR, Ficz G, Oxley D, Krueger F, Reik W, Balasubramanian S (2012) Quantitative sequencing of 5-Methylcytosine and 5-Hydroxymethylcytosine at Single-Base resolution. Science 336:934–937

    Article  CAS  PubMed  Google Scholar 

  17. Bostick M, Kim JK, Estève P-O, Clark A, Pradhan S, Jacobsen SE (2007) UHRF1 plays a role in maintaining DNA methylation in mammalian cells. Science 317:1760–1764

    Article  CAS  PubMed  Google Scholar 

  18. Bourc’his D, Bestor TH (2004) Meiotic catastrophe and retrotransposon reactivation in male germ cells lacking Dnmt3L. Nature 431:96–99

    Article  PubMed  CAS  Google Scholar 

  19. Brenner C, Deplus R, Line Didelot C, Loriot A, Viré E, De Smet C, Gutierrez A, Danovi D, Bernard D, Boon T et al (2005) Myc represses transcription through recruitment of DNA methyltransferase corepressor. EMBO J 24:336–346

    Article  CAS  PubMed  Google Scholar 

  20. Catez F, Ueda T, Bustin M (2006) Determinants of histone H1 mobility and chromatin binding in living cells. Nat Struct Mol Biol 13:305–310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chang Y, Sun L, Kokura K, Horton JR, Fukuda M, Espejo A, Izumi V, Koomen JM, Bedford MT, Zhang X et al (2011) MPP8 mediates the interactions between DNA methyltransferase Dnmt3a and H3K9 methyltransferase GLP/G9a. Nat Commun 2:533

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Chen T, Ueda Y, Xie S, Li E (2002) A novel Dnmt3a isoform produced from an alternative promoter localizes to euchromatin and its expression correlates with active de novo methylation. J Biol Chem 277:38746–38754

    Article  CAS  PubMed  Google Scholar 

  23. Chen T, Ueda Y, Dodge JE, Wang Z, Li E (2003) Establishment and maintenance of genomic methylation patterns in mouse embryonic stem cells by Dnmt3a and Dnmt3b. Mol Cell Biol 23:5594–5605

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chen T, Tsujimoto N, Li E (2004) The PWWP domain of Dnmt3a and Dnmt3b is required for directing DNA methylation to the major satellite repeats at pericentric heterochromatin. Mol Cell Biol 24:9048–9058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Chen ZX, Mann JR, Hsieh CL, Riggs AD, Chédin F (2005) Physical and functional interactions between the human DNMT3L protein and members of the de novo methyltransferase family. J Cell Biochem 95:902–917

    Article  CAS  PubMed  Google Scholar 

  26. Cheng X, Roberts RJ (2001) AdoMet-dependent methylation, DNA methyltransferases and base flipping. Nucleic Acids Res 29:3784–3795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Cheng J, Yang H, Fang J, Ma L, Gong R, Wang P, Li Z, Xu Y (2015) Molecular mechanism for USP7-mediated DNMT1 stabilization by acetylation. Nat Commun 6:7023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Christman JK, Sheikhnejad G, Marasco CJ, Sufrin JR (1995) 5-methyl-2′-deoxycytidine in single-stranded DNA can act in cis to signal de novo DNA methylation. Proc Natl Acad Sci U S A 92:7347–7351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chuang LSH, Ian HI, Koh TW, Ng HH, Xu GL, Li BFL (1997) Human DNA (cytosine-5) methyltransferase PCNA complex as a target for p21 (WAF1). Science 277:1996–2000

    Article  CAS  PubMed  Google Scholar 

  30. Cruickshanks HA, McBryan T, Nelson DM, Vanderkraats ND, Shah PP, van Tuyn J, Singh Rai T, Brock C, Donahue G, Dunican DS et al (2013) Senescent cells harbour features of the cancer epigenome. Nat Cell Biol 15:1495–1506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Datta J, Majumder S, Bai S, Ghoshal K, Kutay H, Smith DS, Crabb JW, Jacob ST (2005) Physical and functional interaction of DNA methyltransferase 3A with Mbd3 and Brg1 in mouse lymphosarcoma cells. Cancer Res 65:10891–10900

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Day K, Waite LL, Thalacker-Mercer A, West A, Bamman MM, Brooks JD, Myers RM, Absher D (2013) Differential DNA methylation with age displays both common and dynamic features across human tissues that are influenced by CpG landscape. Genome Biol 14:R102

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Defossez PA, Stancheva I (2011) Biological functions of methyl-CpG-binding proteins. 1st ed. Elsevier Inc.. Prog Mol Biol Transl Sci 101:377–98. doi: 10.1016/B978-0-12-387685-0.00012-3

  34. Dempster EL, Pidsley R, Schalkwyk LC, Owens S, Georgiades A, Kane F, Kalidindi S, Picchioni M, Kravariti E, Toulopoulou T et al (2011) Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder. Hum Mol Genet 20:4786–4796

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Deplus R, Blanchon L, Rajavelu A, Boukaba A, Defrance M, Luciani J, Rothe F, Dedeurwaerder S, Denis H, Brinkman AB et al (2014) Regulation of DNA methylation patterns by CK2-mediated phosphorylation of Dnmt3a. Cell Rep 8:743–753

    Article  CAS  PubMed  Google Scholar 

  36. Dhayalan A, Rajavelu A, Rathert P, Tamas R, Jurkowska RZ, Ragozin S, Jeltsch A (2010) The Dnmt3a PWWP domain reads histone 3 lysine 36 trimethylation and guides DNA methylation. J Biol Chem 285:26114–26120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Dodget JE, Okano M, Dick F, Tsujimoto N, Chen T, Wang S, Ueda Y, Dyson N, Li E (2005) Inactivation of Dnmt3b in mouse embryonic fibroblasts results in DNA hypomethylation, chromosomal instability, and spontaneous immortalization. J Biol Chem 280:17986–17991

    Article  CAS  Google Scholar 

  38. Du Z, Song J, Wang Y, Zhao Y, Guda K, Yang S, Kao H-Y, Xu Y, Willis J, Markowitz SD et al (2010) DNMT1 stability is regulated by proteins coordinating Deubiquitination and acetylation-driven Ubiquitination. Sci. Signal. 3:ra80

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Easwaran HP, Schermelleh L, Leonhardt H, Cardoso MC (2004) Replication-independent chromatin loading of Dnmt1 during G2 and M phases. EMBO Rep 5:1181–1186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. El Gazzar M, Yoza BK, Chen X, Hu J, Hawkins GA, McCall CE (2008) G9a and HP1 couple histone and DNA methylation to TNFα transcription silencing during endotoxin tolerance. J Biol Chem 283:32198–32208

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Esteller M (2007) Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet 8:286–298

    Article  CAS  PubMed  Google Scholar 

  42. Esteve PO, Terragni J, Deepti K, Chin HG, Dai N, Espejo A, Corr◻a IR, Bedford MT, Pradhan S (2014) Methyllysine reader plant homeodomain (PHD) finger protein 20-like 1 (PHF20L1) antagonizes DNA (cytosine-5) methyltransferase 1 (DNMT1) proteasomal degradation. J Biol Chem 289:8277–8287

    Google Scholar 

  43. Estève P-O, Chang Y, Samaranayake M, Upadhyay AK, Horton JR, Feehery GR, Cheng X, Pradhan S (2011) A methylation and phosphorylation switch between an adjacent lysine and serine determines human DNMT1 stability. Nat Struct Mol Biol 18:42–48

    Article  PubMed  CAS  Google Scholar 

  44. Fahy J, Jeltsch A, Arimondo PB (2012) DNA methyltransferase inhibitors in cancer: a chemical and therapeutic patent overview and selected clinical studies. Expert Opin Ther Pat 22:1–16

    Article  CAS  Google Scholar 

  45. Fatemi M, Hermann A, Pradhan S, Jeltsch A (2001) The activity of the murine DNA methyltransferase Dnmt1 is controlled by interaction of the catalytic domain with the N-terminal part of the enzyme leading to an allosteric activation of the enzyme after binding to methylated DNA. J Mol Biol 309:1189–1199

    Article  CAS  PubMed  Google Scholar 

  46. Felle M, Hoffmeister H, Rothammer J, Fuchs A, Exler JH, Längst G (2011) Nucleosomes protect DNA from DNA methylation in vivo and in vitro. Nucleic Acids Res 39:6956–6969

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Fellinger K, Rothbauer U, Felle M, Längst G, Leonhardt H (2009) Dimerization of DNA methyltransferase 1 is mediated by its regulatory domain. J Cell Biochem 106:521–528

    Article  CAS  PubMed  Google Scholar 

  48. Fuks F, Burgers WA, Godin N, Kasai M, Kouzarides T (2001) Dnmt3a binds deacetylases and is recruited by a sequence-specific repressor to silence transcription. EMBO J 20:2536–2544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Fuks F, Hurd PJ, Deplus R, Kouzarides T (2003) The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase. Nucleic Acids Res 31:2305–2312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Fukuzawa S, Tachibana K, Tajima S, Suetake I (2015) Selective oxidation of 5-hydroxymethylcytosine with micelle incarcerated oxidants to determine it at single base resolution. Bioorganic Med Chem Lett 25:5667–5671

    Article  CAS  Google Scholar 

  51. Fukuzawa S, Takahashi S, Tachibana K, Tajima S, Suetake I (2016) Simple and accurate single base resolution analysis of 5-hydroxymethylcytosine by catalytic oxidative bisulfite sequencing using micelle incarcerated oxidants. Bioorg Med Chem 24:4254–4262

    Article  CAS  PubMed  Google Scholar 

  52. Gardiner-Garden M, Frommer M (1987) CpG Islands in Vertebrate Genomes. JMolBiol 196:261–282

    CAS  Google Scholar 

  53. Garvilles RG, Hasegawa T, Kimura H, Sharif J, Muto M, Koseki H, Takahashi S, Suetake I, Tajima S (2015) Dual functions of the RFTS domain of dnmt1 in replication-coupled DNA methylation and in protection of the genome from aberrant methylation. PLoS One 10:1–19

    Article  CAS  Google Scholar 

  54. Gaudet F, Talbot D, Leonhardt H, Jaenisch R (1998) A short DNA methyltransferase isoform restores methylation in vivo. J Biol Chem 273:32725–32729

    Article  CAS  PubMed  Google Scholar 

  55. Ge YZ, Pu MT, Gowher H, Wu HP, Ding JP, Jeltsch A, Xu GL (2004) Chromatin targeting of de novo DNA methyltransferases by the PWWP domain. J Biol Chem 279:25447–25454

    Article  CAS  PubMed  Google Scholar 

  56. Gelfman S, Cohen N, Yearim A, Ast G (2013) DNA-methylation effect on cotranscriptional splicing is dependent on GC architecture of the exon − intron structure DNA-methylation effect on cotranscriptional splicing is dependent on GC architecture of the exon – intron structure. Genome Res 23:789–799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Goll MG, Kirpekar F, Maggert KA, Yoder JA, Hsieh C-L, Zhang X, Golic KG, Jacobsen SE, Bestor TH (2006) Methylation of tRNAAsp by the DNA methyltransferase homolog Dnmt2. Science 311:395–398

    Article  CAS  PubMed  Google Scholar 

  58. Gopalakrishnan S, Sullivan BA, Trazzi S, Della Valle G, Robertson KD (2009) DNMT3B interacts with constitutive centromere protein CENP-C to modulate DNA methylation and the histone code at centromeric regions. Hum Mol Genet 18:3178–3193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Gowher H, Stockdale CJ, Goyal R, Ferreira H, Owen-Hughes T, Jeltsch A (2005) De novo methylation of nucleosomal DNA by the mammalian Dnmt1 and Dnmt3A DNA methyltransferases. Biochemistry 44:9899–9904

    Article  CAS  PubMed  Google Scholar 

  60. Goyal R, Rathert P, Laser H, Gowher H, Jeltsch A (2007) Phosphorylation of serine-515 activates the mammalian maintenance methyltransferase Dnmt1. Epigenetics 2:155–160

    Article  PubMed  Google Scholar 

  61. Guo JU, Su Y, Zhong C, Ming GL, Song H (2011) Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell 145:423–434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Guo JU, Su Y, Shin JH, Shin J, Li H, Xie B, Zhong C, Hu S, Le T, Fan G et al (2014) Distribution, recognition and regulation of non-CpG methylation in the adult mammalian brain. Nat Neurosci 17:215–222

    Article  CAS  PubMed  Google Scholar 

  63. Guo X, Wang L, Li J, Ding Z, Xiao J, Yin X, He S, Shi P, Dong L, Li G et al (2015) Structural insight into autoinhibition and histone H3-induced activation of DNMT3A. Nature 517:640–644

    Article  CAS  PubMed  Google Scholar 

  64. Handa V, Jeltsch A (2005) Profound flanking sequence preference of Dnmt3a and Dnmt3b mammalian DNA methyltransferases shape the human epigenome. J Mol Biol 348:1103–1112

    Article  CAS  PubMed  Google Scholar 

  65. Hansen RS, Wijmenga C, Luo P, Stanek AM, Canfield TK, Weemaes CM, Gartler SM (1999) The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. Proc Natl Acad Sci U S A 96:14412–14417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Hark AT, Schoenherr CJ, Katz DJ, Ingram RS, Levorse JM, Tilghman SM (2000) CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus. Nature 405:486–489

    Article  CAS  PubMed  Google Scholar 

  67. Harrington MA, Jones PA, Imagawa M, Karin M (1988) Cytosine methylation does not affect binding of transcription factor Sp1. Proc Natl Acad Sci 85:2066–2070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Hashimoto H, Horton JR, Zhang X, Bostick M, Jacobsen SE, Cheng X (2008) The SRA domain of UHRF1 flips 5-methylcytosine out of the DNA helix. Nature 455:826–829

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Hata K, Okano M, Lei H, Li E (2002) Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice. Development 129:1983–1993

    CAS  PubMed  Google Scholar 

  70. Hellman A (2007) Gene body – specific methylation. Science 315:1141–1143

    Article  CAS  PubMed  Google Scholar 

  71. Horii T, Suetake I, Yanagisawa E, Morita S, Kimura M, Nagao Y, Imai H, Tajima S, Hatada I (2011) The Dnmt3b splice variant is specifically expressed in in vitro-manipulated blastocysts and their derivative ES cells. J Reprod Dev 57:579–585

    Article  CAS  PubMed  Google Scholar 

  72. Hu YG, Hirasawa R, Hu JL, Hata K, Li CL, Jin Y, Chen T, Li E, Rigolet M, Viegas-Pequignot E et al (2008) Regulation of DNA methylation activity through Dnmt3L promoter methylation by Dnmt3 enzymes in embryonic development. Hum Mol Genet 17:2654–2664

    Article  CAS  PubMed  Google Scholar 

  73. Iida T, Suetake I, Tajima S, Morioka H, Ohta S, Obuse C, Tsurimoto T (2002) PCNA clamp facilitates action of DNA cytosine methyltransferase 1 on hemimethylated DNA. Genes Cells 7:997–1007

    Article  CAS  PubMed  Google Scholar 

  74. Inano K, Suetake I, Ueda T, Miyake Y, Nakamura M, Okada M, Tajima S (2000) Maintenance-type DNA Methyltransferase is highly expressed in post-mitotic neurons and localized in the cytoplasmic compartment. J Biochem 128:315–321

    Article  CAS  PubMed  Google Scholar 

  75. Jia D, Jurkowska RZ, Zhang X, Jeltsch A, Cheng X (2007) Structure of Dnmt3a bound to Dnmt3L suggests a model for de novo DNA methylation. Nature 449:248–251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Jiang D, Zhang Y, Hart RP, Chen J, Herrup K, Li J (2015) Alteration in 5-hydroxymethylcytosine-mediated epigenetic regulation leads to Purkinje cell vulnerability in ATM deficiency. Brain 138:3520–3536

    Article  PubMed  PubMed Central  Google Scholar 

  77. Jones P, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3:415–428

    Article  CAS  PubMed  Google Scholar 

  78. Jung M, Pfeifer GP (2015) Aging and DNA methylation. BMC Biol 13:7

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Kafer GR, Li X, Horii T, Suetake I, Tajima S, Hatada I, Carlton PM, Kafer GR, Li X, Horii T et al (2016) 5-Hydroxymethylcytosine marks sites of DNA damage and promotes genome stability 5-Hydroxymethylcytosine marks sites of DNA damage and promotes genome stability. Cell Rep 14:1283–1292

    Article  CAS  PubMed  Google Scholar 

  80. Kameshita I, Sekiguchi M, Hamasaki D, Sugiyama Y, Hatano N, Suetake I, Tajima S, Sueyoshi N (2008) Cyclin-dependent kinase-like 5 binds and phosphorylates DNA methyltransferase 1. Biochem Biophys Res Commun 377:1162–1167

    Article  CAS  PubMed  Google Scholar 

  81. Kaneda M, Okano M, Hata K, Sado T, Tsujimoto N, Li E, Sasaki H (2004) Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting. Nature 429:900–903

    Article  CAS  PubMed  Google Scholar 

  82. Kang ES, Chang W, Jae H (2001) Dnmt3b, de novo DNA Methyltransferase, interacts with SUMO-1 and Ubc9 through its N-terminal region and is subject to modification by SUMO-1. Biochem Biophys Res Commun 289:862–868

    Article  CAS  PubMed  Google Scholar 

  83. Kangaspeska S, Stride B, Métivier R, Polycarpou-Schwarz M, Ibberson D, Carmouche RP, Benes V, Gannon F, Reid G (2008) Transient cyclical methylation of promoter DNA. Nature 452:112–115

    Article  CAS  PubMed  Google Scholar 

  84. Kim GD, Ni J, Kelesoglu N, Roberts RJ, Pradhan S (2002) Co-operation and communication between the human maintenance and de novo DNA (cytosine-5) methyltransferases. EMBO J 21:4183–4195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Klimasauskas S, Kumar S, Roberts RJ, Cheng X (1994) Hhal methyltransferase flips its target base out of the DNA helix. Cell 76:357–369

    Article  CAS  PubMed  Google Scholar 

  86. Kohli RM, Zhang Y (2013) TET enzymes, TDG and the dynamics of DNA demethylation. Nature 502:472–479

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Kotini AG, Mpakali A, Agalioti T (2011) Dnmt3a1 upregulates transcription of distinct genes and targets chromosomal gene clusters for epigenetic silencing in mouse embryonic stem cells. Mol Cell Biol 31:1577–1592

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Kriukienė E, Liutkevičiūtė Z, Klimašauskas S (2012) 5-Hydroxymethylcytosine--the elusive epigenetic mark in mammalian DNA. Chem Soc Rev 41:6916–6930

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Kuck D, Singh N, Lyko F, Medina-Franco JL (2010) Novel and selective DNA methyltransferase inhibitors: docking-based virtual screening and experimental evaluation. Bioorganic Med Chem 18:822–829

    Article  CAS  Google Scholar 

  90. Kudo Y, Tateishi K, Yamamoto K, Yamamoto S, Asaoka Y, Ijichi H, Nagae G, Yoshida H, Aburatani H, Koike K (2012) Loss of 5-hydroxymethylcytosine is accompanied with malignant cellular transformation. Cancer Sci 103:670–676

    Article  CAS  PubMed  Google Scholar 

  91. Kumar D, Lassar AB (2014) Fibroblast growth factor maintains Chondrogenic potential of limb bud Mesenchymal cells by modulating DNMT3A recruitment. Cell Rep 8:1419–1431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Kumar S, Cheng X, Klimasauskas S, Mi S, Posfai J, Roberts RJ, Wilson GG (1994) The DNA (cytosine-5) methyltransferases. Nucleic Acids Res 22:1–10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Laurent L, Wong E, Li G, Laurent L, Wong E, Li G, Huynh T, Tsirigos A, Ong CT, Low HM et al (2010) Dynamic changes in the human methylome during differentiation dynamic changes in the human methylome during differentiation. Genome Res 20:320–331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Lavoie G, St-Pierre Y (2011) Phosphorylation of human DNMT1: implication of cyclin-dependent kinases. Biochem Biophys Res Commun 409:187–192

    Article  CAS  PubMed  Google Scholar 

  95. Lee B, Muller MT (2009) SUMOylation enhances DNA methylation activity. Biochem J 421:449–461

    Article  CAS  PubMed  Google Scholar 

  96. Leonhardt H, Page AW, Weier HU, Bestor TH (1992) A targeting sequence directs DNA methyltransferase to sites of DNA replication in mammalian nuclei. Cell 71:865–873

    Article  CAS  PubMed  Google Scholar 

  97. Lev Maor G, Yearim A, Ast G (2015) The alternative role of DNA methylation in splicing regulation. Trends Genet 31:274–280

    Article  CAS  PubMed  Google Scholar 

  98. Li W, Liu M (2011) Distribution of 5-Hydroxymethylcytosine in Different human tissues. Journal of Nucleic Acids 2011:1–5

    Article  CAS  Google Scholar 

  99. Li Y, Zhu B (2014) Acute myeloid leukemia with DNMT3A mutations. Leuk Lymphoma 55:2002–2012

    Article  CAS  PubMed  Google Scholar 

  100. Li E, Bestor TH, Jaenisch R (1992) Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69:915–926

    Article  CAS  PubMed  Google Scholar 

  101. Li B-Z, Huang Z, Cui Q-Y, Song X-H, Du L, Jeltsch A, Chen P, Li G, Li E, Xu G-L (2011) Histone tails regulate DNA methylation by allosterically activating de novo methyltransferase. Cell Res 21:1172–1181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Liang G, Chan MF, Tomigahara Y, Tsai YC, Gonzales FA, Li E, Laird PW, Jones PA (2002) Cooperativity between DNA methyltransferases in the maintenance methylation of repetitive elements. Mol Cell Biol 22:480–491

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Liao J, Karnik R, Gu H, Ziller MJ, Clement K, Tsankov AM, Akopian V, Gifford C a, Donaghey J, Galonska C et al (2015) Targeted disruption of DNMT1, DNMT3A and DNMT3B in human embryonic stem cells. Nat Genet 47:469–478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Lin IG, Han L, Taghva A, O’Brien LE, Hsieh C-L (2002) Murine de novo methyltransferase Dnmt3a demonstrates strand asymmetry and site preference in the methylation of DNA in vitro. Mol Cell Biol 22:704–723

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Lin Y, Fan H, Frederiksen M, Zhao K, Jiang L, Wang Z, Zhou S, Guo W, Gao J, Li S et al (2012) Detecting S-adenosyl-l-methionine-induced conformational change of a histone methyltransferase using a homogeneous time-resolved fluorescence-based binding assay. Anal Biochem 423:171–177

    Article  CAS  PubMed  Google Scholar 

  106. Ling Y, Sankpal UT, Robertson AK, McNally JG, Karpova T, Robertson KD (2004) Modification of de novo DNA methyltransferase 3a (Dnmt3a) by SUMO-1 modulates its interaction with histone deacetylases (HDACs) and its capacity to repress transcription. Nucleic Acids Res 32:598–610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Lister R, Pelizzola M, Dowen RH, Hawkins RD, Hon G, Tonti-Filippini J, Nery JR, Lee L, Ye Z, Ngo Q-M et al (2009) Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462:315–322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Lister R, Pelizzola M, Kida YS, Hawkins RD, Nery JR, Hon G, Antosiewicz-Bourget J, O’Malley R, Castanon R, Klugman S et al (2011) Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature 471:68–73

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Liu Y, Sun L, Jost JP (1996) In differentiating mouse myoblasts DNA methyltransferase is posttranscriptionally and posttranslationally regulated. Nucleic Acids Res 24:2718–2722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Liu Y, Aryee MJ, Padyukov L, Fallin MD, Hesselberg E, Runarsson A, Reinius L, Acevedo N, Taub M, Ronninger M et al (2013) Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis. Nat Biotechnol 31:142–147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Liu Y, Zhang X, Blumenthal RM, Cheng X (2013) A common mode of recognition for methylated CpG. Trends Biochem Sci 38:177–183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Lorincz MC, Schübeler D, Hutchinson SR, Dickerson DR, Groudine M (2002) DNA methylation density influences the stability of an epigenetic imprint and Dnmt3a/b-independent de novo methylation. Mol Cell Biol 22:7572–7580

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Ma P, de Waal E, Weaver JR, Bartolomei MS, Schultz RM (2015) A DNMT3A2-HDAC2 complex is essential for genomic imprinting and genome integrity in mouse oocytes. Cell Rep 13:1552–1560

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Meissner A, Gnirke A, Bell GW, Ramsahoye B, Lander ES, Jaenisch R (2005) Reduced representation bisulfite sequencing for comparative high-resolution DNA methylation analysis. Nucleic Acids Res 33:5868–5877

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Mertineit C, Yoder JA, Taketo T, Laird DW, Trasler JM, Bestor TH (1998) Sex-specific exons control DNA methyltransferase in mammalian germ cells. Development 125:889–897

    CAS  PubMed  Google Scholar 

  116. Métivier R, Gallais R, Tiffoche C, Le Péron C, Jurkowska RZ, Carmouche RP, Ibberson D, Barath P, Demay F, Reid G et al (2008) Cyclical DNA methylation of a transcriptionally active promoter. Nature 452:45–50

    Article  PubMed  CAS  Google Scholar 

  117. Miller CA, Sweatt JD (2007) Covalent modification of DNA regulates memory formation. Neuron 53:857–869

    Article  CAS  PubMed  Google Scholar 

  118. Misaki T, Yamaguchi L, Sun J, Orii M, Nishiyama A, Nakanishi M (2016) The replication foci targeting sequence (RFTS) of DNMT1 functions as a potent histone H3 binding domain regulated by autoinhibition. Biochem Biophys Res Commun 470:741–747

    Article  CAS  PubMed  Google Scholar 

  119. Myrianthopoulos V, Cartron PF, Liutkevičiūtė Z, Klimašauskas S, Matulis D, Bronner C, Martinet N, Mikros E (2016) Tandem virtual screening targeting the SRA domain of UHRF1 identifies a novel chemical tool modulating DNA methylation. Eur J Med Chem 114:390–396

    Article  CAS  PubMed  Google Scholar 

  120. Neri F, Krepelova A, Incarnato D, Maldotti M, Parlato C, Galvagni F, Matarese F, Stunnenberg HG, Oliviero S (2013) XDnmt3L antagonizes DNA methylation at bivalent promoters and favors DNA methylation at gene bodies in ESCs. Cell 155:121–134

    Article  CAS  PubMed  Google Scholar 

  121. Nishiyama A, Yamaguchi L, Sharif J, Johmura Y, Kawamura T, Nakanishi K, Shimamura S, Arita K, Kodama T, Ishikawa F et al (2013) Uhrf1-dependent H3K23 ubiquitylation couples maintenance DNA methylation and replication. Nature 502:249–253

    Article  CAS  PubMed  Google Scholar 

  122. Oakes CC, Smiraglia DJ, Plass C, Trasler JM, Robaire B (2003) Aging results in hypermethylation of ribosomal DNA in sperm and liver of male rats. Proc Natl Acad Sci U S A 100:1775–1780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Okano M, Bell DW, Haber DA (1999) DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99:247–257

    Article  CAS  PubMed  Google Scholar 

  124. Okuwaki M, Verreault A (2004) Maintenance DNA methylation of nucleosome Core particles. J Biol Chem 279:2904–2912

    Article  CAS  PubMed  Google Scholar 

  125. Ooi SKT, Qiu C, Bernstein E, Li K, Jia D, Yang Z, Erdjument-Bromage H, Tempst P, Lin S-P, Allis CD et al (2007) DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature 448:714–717

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Ostler KR, Davis EM, Payne SL, Gosalia BB, Expósito-Céspedes J, Le Beau MM, Godley LA (2007) Cancer cells express aberrant DNMT3B transcripts encoding truncated proteins. Oncogene 26:5553–5563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Otani J, Nankumo T, Arita K, Inamoto S, Ariyoshi M, Shirakawa M (2009) Structural basis for recognition of H3K4 methylation status by the DNA methyltransferase 3A ATRX-DNMT3-DNMT3L domain. EMBO Rep 10:1235–1241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Otani J, Kimura H, Sharif J, Endo TA, Mishima Y, Kawakami T, Koseki H, Shirakawa M, Suetake I, Tajima S (2013) Cell cycle-dependent turnover of 5-hydroxymethyl cytosine in mouse embryonic stem cells. PLoS One 8:1–11

    Article  CAS  Google Scholar 

  129. Pedroso JL, Povoas Barsottini OG, Lin L, Melberg A, Oliveira ASB, Mignot E (2013) A novel de novo exon 21 DNMT1 mutation causes cerebellar ataxia, deafness, and narcolepsy in a Brazilian patient. Sleep 36(1257–9):1259A

    Google Scholar 

  130. Pidsley R, Viana J, Hannon E, Spiers H, Troakes C, Al-Saraj S, Mechawar N, Turecki G, Schalkwyk LC, Bray NJ et al (2014) Methylomic profiling of human brain tissue supports a neurodevelopmental origin for schizophrenia. Genome Biol 15:483

    Article  PubMed  PubMed Central  Google Scholar 

  131. Portela A, Esteller M (2010) Epigenetic modifications and human disease. Nat Biotechnol 28:1057–1068

    Article  CAS  PubMed  Google Scholar 

  132. Pradhan M, Estève PO, Hang GC, Samaranayke M, Kim GD, Pradhan S (2008) CXXC domain of human DNMT1 is essential for enzymatic activity. Biochemistry 47:10000–10009

    Article  CAS  PubMed  Google Scholar 

  133. Pradhan S, Chin HG, Estève PO, Jacobsen SE (2009) SET7/9 mediated methylation of non-histone proteins in mammalian cells. Epigenetics 4:383–387

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Prendergast GC, Ziff EB (1991) Methylation-sensitive sequence-specific DNA binding by the c-Myc basic region. Science 251:186–189

    Article  CAS  PubMed  Google Scholar 

  135. Purdy MM, Holz-Schietinger C, Reich NO (2010) Identification of a second DNA binding site in human DNA methyltransferase 3A by substrate inhibition and domain deletion. Arch Biochem Biophys 498:13–22

    Article  CAS  PubMed  Google Scholar 

  136. Qin W, Wolf P, Liu N, Link S, Smets M, Mastra FL, Forné I, Pichler G, Hörl D, Fellinger K et al (2015) DNA methylation requires a DNMT1 ubiquitin interacting motif (UIM) and histone ubiquitination. Cell Res 25:911–929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Qiu C, Sawada K, Zhang X, Cheng X (2002) The PWWP domain of mammalian DNA methyltransferase Dnmt3b defines a new family of DNA-binding folds. Nat Struct Biol 9:217–224

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Quenneville S, Verde G, Corsinotti A, Kapopoulou A, Jakobsson J, Offner S, Baglivo I, Pedone PV, Grimaldi G, Riccio A et al (2011) 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Quenneville S, Turelli P, Bojkowska K, Raclot C, Offner S, Kapopoulou A, Trono D (2012) The KRAB-ZFP/KAP1 system contributes to the early embryonic establishment of site-specific DNA methylation patterns maintained during development. Cell Rep 2:766–773

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Radman-Livaja M, Rando OJ (2010) Nucleosome positioning: how is it established, and why does it matter? Dev Biol 339:258–266

    Article  CAS  PubMed  Google Scholar 

  141. Ramsahoye BH, Biniszkiewicz D, Lyko F, Clark V, Bird AP, Jaenisch R (2000) Non-CpG methylation is prevalent in embryonic stem cells and may be mediated by DNA methyltransferase 3a. Proc Natl Acad Sci U S A 97:5237–5242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Robertson KD (2005) DNA methylation and human disease. Nat Rev Genet 6:597–610

    Article  CAS  PubMed  Google Scholar 

  143. Robertson KD, Uzvolgyi E, Liang G, Talmadge C, Sumegi J, Gonzales FA, Jones PA (1999) The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors. Nucleic Acids Res 27:2291–2298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Robertson AK, Geiman TM, Sankpal UT, Hager GL, Robertson KD (2004) Effects of chromatin structure on the enzymatic and DNA binding functions of DNA methyltransferases DNMT1 and Dnmt3a in vitro. Biochem Biophys Res Commun 322:110–118

    Article  CAS  PubMed  Google Scholar 

  145. Ross JP, Suetake I, Tajima S, Molloy PL (2010) Recombinant mammalian DNA methyltransferase activity on model transcriptional gene silencing short RNA-DNA heteroduplex substrates. Biochem J 432:323–332

    Article  CAS  PubMed  Google Scholar 

  146. Rothbart SB, Dickson BM, Ong MS, Krajewski K, Houliston S, Kireev DB, Arrowsmith CH, Strahl BD (2013) 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Rountree MR, Bachman KE, Baylin SB (2000) DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. Nat Genet 25:269–277

    Article  CAS  PubMed  Google Scholar 

  148. Rush M, Appanah R, Lee S, Lam LL, Goyal P, Lorincz MC (2009) Targeting of EZH2 to a defined genomic site is sufficient for recruitment of Dnmt3a but not de novo DNA methylation. Epigenetics 4:404–414

    Article  CAS  PubMed  Google Scholar 

  149. Saitou M, Kagiwada S, Kurimoto K (2012) Epigenetic reprogramming in mouse pre-implantation development and primordial germ cells. Development 139:15–31

    Article  CAS  PubMed  Google Scholar 

  150. Sakai Y, Suetake I, Shinozaki F, Yamashina S, Tajima S (2004) Co-expression of de novo DNA methyltransferases Dnmt3a2 and Dnmt3L in gonocytes of mouse embryos. Gene Expr Patterns 5:231–237

    Article  CAS  PubMed  Google Scholar 

  151. Sato N, Kondo M, Arai K (2006) The orphan nuclear receptor GCNF recruits DNA methyltransferase for Oct-3/4 silencing. Biochem Biophys Res Commun 344:845–851

    Article  CAS  PubMed  Google Scholar 

  152. Schermelleh L, Spada F, Easwaran HP, Zolghadr K, Margot JB, Cardoso MC, Leonhardt H (2005) Trapped in action: direct visualization of DNA methyltransferase activity in living cells. Nat Methods 2:751–756

    Article  CAS  PubMed  Google Scholar 

  153. Schmitz KM, Mayer C, Postepska A, Grummt I (2010) Interaction of noncoding RNA with the rDNA promoter mediates recruitment of DNMT3b and silencing of rRNA genes. Genes Dev 24:2264–2269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Schrader A, Gross T, Thalhammer V, Langst G (2015) Characterization of Dnmt1 binding and DNA methylation on nucleosomes and nucleosomal arrays. PLoS One 10:e0140076

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  155. Senyuk V, Premanand K, Xu P, Qian Z, Nucifora G (2011) The oncoprotein EVI1 and the DNA methyltransferase Dnmt3 co-operate in binding and de novo methylation of target DNA. PLoS One 6:e0020793

    Article  CAS  Google Scholar 

  156. Shamay M, Greenway M, Liao G, Ambinder RF, Hayward SD (2010) De novo DNA methyltransferase DNMT3b interacts with NEDD8-modified proteins. J Biol Chem 285:36377–36386

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Sharif J, Muto M, Takebayashi S, Suetake I, Iwamatsu A, Endo T a, Shinga J, Mizutani-Koseki Y, Toyoda T, Okamura K et al (2007) The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA. Nature 450:908–912

    Article  CAS  PubMed  Google Scholar 

  158. Shen L, Zhang Y (2013) 5-Hydroxymethylcytosine: generation, fate, and genomic distribution. Curr Opin Cell Biol 25:289–296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Shirane K, Toh H, Kobayashi H, Miura F, Chiba H, Ito T, Kono T, Sasaki H (2013) Mouse oocyte Methylomes at base resolution reveal genome-wide accumulation of non-CpG methylation and role of DNA Methyltransferases. PLoS Genet 9:e1003439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Smallwood SA, Kelsey G (2012) De novo DNA methylation: a germ cell perspective. Trends Genet 28:33–42

    Article  CAS  PubMed  Google Scholar 

  161. Smallwood A, Estève PO, Pradhan S, Carey M (2007) Functional cooperation between HP1 and DNMT1 mediates gene silencing. Genes Dev 21:1169–1178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Smith ZD, Meissner A (2013) DNA methylation: roles in mammalian development. Nat Rev Genet 14:204–220

    Article  CAS  PubMed  Google Scholar 

  163. Song J, Rechkoblit O, Bestor TH, Patel DJ (2011) Structure of DNMT1-DNA complex reveals a role for autoinhibition in maintenance DNA methylation. Science 331:1036–1040

    Article  CAS  PubMed  Google Scholar 

  164. Song J, Teplova M, Ishibe-Murakami S, Patel DJ (2012) Structure-based mechanistic insights into DNMT1-mediated maintenance DNA methylation. Science 335:709–712

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Stewart KR, Veselovska L, Kim J, Huang J, Saadeh H, Tomizawa S, Smallwood SA, Chen T, Kelsey G (2015) Dynamic changes in histone modifications precede de novo DNA methylation in oocytes. Genes Dev 29:2449–2462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Stroud H, Do T, Du J, Zhong X, Feng S, Johnson L, Patel DJ, Jacobsen SE (2014) Non-CG methylation patterns shape the epigenetic landscape in Arabidopsis. Nat Struct Mol Biol 21:64–72

    Article  CAS  PubMed  Google Scholar 

  167. Suetake I, Miyazaki J, Murakami C, Takeshima H, Tajima S (2003) Distinct enzymatic properties of recombinant mouse DNA methyltransferases Dnmt3a and Dnmt3b. J Biochem 133:737–744

    Article  CAS  PubMed  Google Scholar 

  168. Suetake I, Shinozaki F, Miyagawa J, Takeshima H, Tajima S (2004) DNMT3L stimulates the DNA methylation activity of Dnmt3a and Dnmt3b through a direct interaction. J Biol Chem 279:27816–27823

    Article  CAS  PubMed  Google Scholar 

  169. Suetake I, Morimoto Y, Fuchikami T, Abe K, Tajima S (2006) Stimulation effect of Dnmt3L on the DNA methylation activity of Dnmt3a2. J Biochem 140:553–559

    Article  CAS  PubMed  Google Scholar 

  170. Suetake I, Hayata D, Tajima S (2006) The amino-terminus of mouse DNA methyltransferase 1 forms an independent domain and binds to DNA with the sequence involving PCNA binding motif. J Biochem 140:763–776

    Article  CAS  PubMed  Google Scholar 

  171. Suetake I, Mishima Y, Kimura H, Lee Y-H, Goto Y, Takeshima H, Ikegami T, Tajima S (2011) Characterization of DNA-binding activity in the N-terminal domain of the DNA methyltransferase Dnmt3a. Biochem J 437:141–148

    Article  CAS  PubMed  Google Scholar 

  172. Sugiyama Y, Hatano N, Sueyoshi N, Suetake I, Tajima S, Kinoshita E, Kinoshita-Kikuta E, Koike T, Kameshita I (2010) The DNA-binding activity of mouse DNA methyltransferase 1 is regulated by phosphorylation with casein kinase 1delta/epsilon. Biochem J 427:489–497

    Article  CAS  PubMed  Google Scholar 

  173. Sun D, Luo M, Jeong M, Rodriguez B, Xia Z, Hannah R, Wang H, Le T, Faull KF, Chen R et al (2014) Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal. Cell Stem Cell 14:673–688

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Suzuki MM, Bird A (2008) DNA methylation landscapes: provocative insights from epigenomics. Nat Rev Genet 9:465–476

    Article  CAS  PubMed  Google Scholar 

  175. Syeda F, Fagan RL, Wean M, Avvakumov GV, Walker JR, Xue S, Dhe-Paganon S, Brenner C (2011) The replication focus targeting sequence (RFTS) domain is a DNA-competitive inhibitor of Dnmt1. J Biol Chem 286:15344–15351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Takagi H, Tajima S, Asano A (1995) Overexpression of DNA methyltransferase in myoblast cells accelerates myotube formation. Eur J Biochem 231:282–291

    Article  CAS  PubMed  Google Scholar 

  177. Takahashi S, Suetake I, Engelhardt J, Tajima S (2015) A novel method to analyze 5-hydroxymethylcytosine in CpG sequences using maintenance DNA methyltransferase, DNMT1. FEBS Open Bio 5:741–747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Takeshima H, Suetake I, Shimahara H, Ura K, Tate SI, Tajima S (2006) Distinct DNA methylation activity of Dnmt3a and Dnmt3b towards naked and nucleosomal DNA. J Biochem 139:503–515

    Article  CAS  PubMed  Google Scholar 

  179. Takeshima H, Suetake I, Tajima S (2008) Mouse Dnmt3a preferentially Methylates linker DNA and is inhibited by histone H1. J Mol Biol 383:810–821

    Article  CAS  PubMed  Google Scholar 

  180. Takeshita K, Suetake I, Yamashita E, Suga M, Narita H, Nakagawa A, Tajima S (2011) Structural insight into maintenance methylation by mouse DNA methyltransferase 1 (Dnmt1). Proc Natl Acad Sci U S A 108:9055–9059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Tamaru H, Selker EU (2001) A histone H3 methyltransferase controls DNA methylation in Neurospora crassa. Nature 414:277–283

    Article  CAS  PubMed  Google Scholar 

  182. Teif VB, Beshnova DA, Vainshtein Y, Marth C, Mallm JP, Rippe TH (2014) Nucleosome repositioning links DNA (de)methylation and differential CTCF binding during stem cell development. Genome Res 24:1285–1295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Umezawa A, Yamamoto H, Rhodes K, Klemsz MJ, Maki R a, Oshima RG (1997) Methylation of an ETS site in the intron enhancer of the keratin 18 gene participates in tissue-specific repression. Mol Cell Biol 17:4885–4894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Ushijima T, Watanabe N, Okochi E, Kaneda A, Sugimura T, Miyamoto K (2003) Fidelity of the methylation pattern and its variation in the genome. Genome Res 13:868–874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Valinluck V, Sowers LC (2007) Endogenous cytosine damage products alter the site selectivity of human DNA maintenance methyltransferase DNMT1. Cancer Res 67:946–950

    Article  CAS  PubMed  Google Scholar 

  186. Van Emburgh BO, Robertson KD (2011) Modulation of Dnmt3b function in vitro by interactions with Dnmt3L, Dnmt3a and Dnmt3b splice variants. Nucleic Acids Res 39:4984–5002

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  187. Vertino PM, Yen RW, Gao J, Baylin SB (1996) De novo methylation of CpG island sequences in human fibroblasts overexpressing DNA (cytosine-5-)-methyltransferase. Mol Cell Biol 16:4555–4565

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Vilkaitis G, Suetake I, Klimasauskas S, Tajima S (2005) Processive methylation of hemimethylated CpG sites by mouse Dnmt1 DNA methyltransferase. J Biol Chem 280:64–72

    Article  CAS  PubMed  Google Scholar 

  189. Viré E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C, Morey L, Van Eynde A, Bernard D, Vanderwinden J-M et al (2005) The Polycomb group protein EZH2 directly controls DNA methylation. Nature 439:871–874

    Article  PubMed  CAS  Google Scholar 

  190. Wang YA, Kamarova Y, Shen KC, Jiang Z, Hahn MJ, Wang Y, Brooks SC (2005) DNA methyltransferase-3a interacts with p53 and represses p53-mediated gene expression. Cancer Biol Ther 4:1138–1143

    Article  CAS  PubMed  Google Scholar 

  191. Watanabe D, Suetake I, Tada T, Tajima S (2002) Stage- and cell-specific expression of Dnmt3a and Dnmt3b during embryogenesis. Mech Dev 118:187–190

    Article  CAS  PubMed  Google Scholar 

  192. Watanabe D, Suetake I, Tajima S, Hanaoka K (2004) Expression of Dnmt3b in mouse hematopoietic progenitor cells and spermatogonia at specific stages. Gene Expr Patterns 5:43–49

    Article  CAS  PubMed  Google Scholar 

  193. Webster KE, O’Bryan MK, Fletcher S, Crewther PE, Aapola U, Craig J, Harrison DK, Aung H, Phutikanit N, Lyle R et al (2005) Meiotic and epigenetic defects in Dnmt3L-knockout mouse spermatogenesis. Proc Natl Acad Sci U S A 102:4068–4073

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Weisenberger DJ, Velicescu M, Preciado-Lopez MA, Gonzales FA, Tsai YC, Liang G, Jones PA (2002) Identification and characterization of alternatively spliced variants of DNA methyltransferase 3a in mammalian cells. Gene 298:91–99

    Article  CAS  PubMed  Google Scholar 

  195. Weisenberger DJ, Velicescu M, Cheng JC, Gonzales F a, Liang G, Jones P a (2004) Role of the DNA methyltransferase variant DNMT3b3 in DNA methylation. Mol Cancer Res 2:62–72

    CAS  PubMed  Google Scholar 

  196. Winkelmann J, Lin L, Schormair B, Kornum BR, Faraco J, Plazzi G, Melberg A, Cornelio F, Urban AE, Pizza F et al (2012) Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy. Hum Mol Genet 21:2205–2210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Wu TP, Wang T, Seetin MG, Lai Y, Zhu S, Lin K, Liu Y, Byrum SD, Mackintosh SG, Zhong M, Tackett A, Wang G, Hon LS, Fang G, Swenberg JA, Xiao AZ (2016) DNA methylation on N6-adenine in mammalian embryonic stem cells. Nature 532:329–333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Xie W, Barr CL, Kim A, Yue F, Lee AY, Eubanks J, Dempster EL, Ren B (2012) Base-resolution analyses of sequence and parent-of-origin dependent DNA methylation in the mouse genome. Cell 148:816–831

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Xu GL, Bestor TH, Bourc’his D, Hsieh CL, Tommerup N, Bugge M, Hulten M, Qu X, Russo JJ, Viegas-Péquignot E (1999) Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature 402:187–191

    Article  CAS  PubMed  Google Scholar 

  200. Yang H, Liu Y, Bai F, Zhang JY, Ma SH, Liu J, Xu ZD, Zhu HG, Ling ZQ, Ye D, Guan KL, Xiong Y (2013) Tumor development is associated with decrease of TET gene expression and 5-methylcytosine hydroxylation. Oncogene 32:663–669

    Article  CAS  PubMed  Google Scholar 

  201. Yang S-M, Kim BJ, Norwood Toro L, Skoultchi AI (2013) H1 linker histone promotes epigenetic silencing by regulating both DNA methylation and histone H3 methylation. Proc Natl Acad Sci 110:1708–1713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Yang J, Guo R, Wang H, Ye X, Zhou Z, Dan J, Wang H, Gong P, Deng W, Yin Y, Mao S, Wang L, Ding J, Li J, Keefe DL, Dawlaty MM, Wang J, Xu G, Liu L (2016) Tet enzymes regulate telomere maintenance and chromosomal stability of mouse ESCs. Cell Rep 15:1809–1821

    Article  CAS  PubMed  Google Scholar 

  203. Yoder JA, Bestor TH (1998) A candidate mammalian DNA methyltransferase related to pmt1p of fission yeast. Hum Mol Genet 7:279–284

    Article  CAS  PubMed  Google Scholar 

  204. Yu M, Hon GC, Szulwach KE, Song C, Zhang L, Kim A, Li X, Dai Q, Shen Y, Park B et al (2012) Resource Base-resolution analysis of 5-Hydroxymethylcytosine in the mammalian genome. Cell 149:1368–1380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Zemach A, Kim MY, Hsieh PH, Coleman-Derr D, Eshed-Williams L, Thao K, Harmer SL, Zilberman D (2013) The arabidopsis nucleosome remodeler DDM1 allows DNA methyltransferases to access H1-containing heterochromatin. Cell 153:193–205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Zhang Y, Jurkowska R, Soeroes S, Rajavelu A, Dhayalan A, Bock I, Rathert P, Brandt O, Reinhardt R, Fischle W et al (2010) 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Zhang Z-M, Liu S, Lin K, Luo Y, Perry JJ, Wang Y, Song J (2015) Crystal structure of human DNA Methyltransferase 1. J Mol Biol 427:2520–2531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Zhao Q, Rank G, Tan YT, Li H, Moritz RL, Simpson RJ, Cerruti L, Curtis DJ, Patel DJ, Allis CD et al (2009) PRMT5-mediated methylation of histone H4R3 recruits DNMT3A, coupling histone and DNA methylation in gene silencing. Nat Struct Mol Biol 16:304–311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Zhu H, Geiman TM, Xi S, Jiang Q, Schmidtmann A, Chen T, Li E, Muegge K (2006) Lsh is involved in de novo methylation of DNA. EMBO J 25:335–345

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Ziller MJ, Gu H, Müller F, Donaghey J, Tsai LT-Y, Kohlbacher O, De Jager PL, Rosen ED, Bennett DA, Bernstein BE et al (2013) Charting a dynamic DNA methylation landscape of the human genome. Nature 500:477–481

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Zuo X, Sheng J, Lau HT, McDonald CM, Andrade M, Cullen DE, Bell FT, Iacovino M, Kyba M, Xu G et al (2012) Zinc finger protein ZFP57 requires its co-factor to recruit DNA methyltransferases and maintains DNA methylation imprint in embryonic stem cells via its transcriptional repression domain. J Biol Chem 287:2107–2118

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Isao Suetake .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Suetake, I., Watanebe, M., Takeshita, K., Takahashi, S., Carlton, P. (2017). The Molecular Basis of DNA Methylation. In: Kaneda, A., Tsukada, Yi. (eds) DNA and Histone Methylation as Cancer Targets. Cancer Drug Discovery and Development. Humana Press, Cham. https://doi.org/10.1007/978-3-319-59786-7_2

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-59786-7_2

  • Published:

  • Publisher Name: Humana Press, Cham

  • Print ISBN: 978-3-319-59784-3

  • Online ISBN: 978-3-319-59786-7

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics