Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

DNA methylation and chromatin – unraveling the tangled web

Oncogene volume 21, pages 5361–5379 (2002)Cite this article

Abstract

Methylation of cytosines within the CpG dinucleotide by DNA methyltransferases is involved in regulating transcription and chromatin structure, controlling the spread of parasitic elements, maintaining genome stability in the face of vast amounts of repetitive DNA, and X chromosome inactivation. Cellular DNA methylation is highly compartmentalized over the mammalian genome and this compartmentalization is essential for embryonic development. When the complicated mechanisms that control which DNA sequences become methylated go awry, a number of inherited genetic diseases and cancer may result. Much new information has recently come to light regarding how cellular DNA methylation patterns may be established during development and maintained in somatic cells. Emerging evidence indicates that various chromatin states such as histone modifications (acetylation and methylation) and nucleosome positioning (modulated by ATP-dependent chromatin remodeling machines) determine DNA methylation patterning. Additionally, various regulatory factors interacting with the DNA methyltransferases may direct them to specific DNA sequences, regulate their enzymatic activity, and allow their use as transcriptional repressors. Continued studies of the connections between DNA methylation and chromatin structure and the DNA methyltransferase-associated proteins, will likely reveal that many, if not all, epigenetic modifications of the genome are directly connected. Such studies should also yield new insights into treating diseases involving aberrant DNA methylation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 4
Figure 2
Figure 3
Figure 5
Figure 6

Similar content being viewed by others

References

  • Aapola U, Lyle R, Krohn K, Antonarakis SE, Peterson P . 2001 Cytogenet. Cell Genet. 92: 122–126

  • Aapola U, Shibuya K, Scott HS, Ollila J, Vihinen M, Heino M, Shintani A, Kawasaki K, Minoshima S, Krohn K, Antonarakis SE, Shimizu N, Kudoh J, Peterson P . 2000 Genomics 65: 293–298

  • Aguirre-Arteta AM, Grunewald I, Cardoso MC, Leonhardt H . 2000 Cell Growth Differ. 11: 551–559

  • Aoki A, Suetake I, Miyagawa J, Fujio T, Chijiwa T, Sasaki H, Tajima S . 2001 Nucleic Acids Res. 29: 3506–3512

  • Aoki K, Meng G, Suzuki K, Takashi T, Kameoka Y, Nakahara K, Ishida R, Kasai M . 1998 J. Biol. Chem. 273: 26698–26704

  • Bachman KE, Rountree MR, Baylin SB . 2001 J. Biol. Chem. 276: 32282–32287

  • Bacolla A, Pradhan S, Roberts RJ, Wells RD . 1999 J. Biol. Chem. 274: 33011–33019

  • Baylin SB, Esteller M, Rountree MR, Bachman KE, Schuebel K, Herman JG . 2001 Hum. Mol. Genet. 10: 687–692

  • Beard C, Li E, Jaenisch R . 1995 Genes. Dev. 9: 2325–2334

  • Berube NG, Smeenk CA, Picketts DJ . 2000 Hum. Mol. Genet. 9: 539–547

  • Bestor T, Laudano A, Mattaliano R, Ingram V . 1988 J. Mol. Biol. 203: 971–983

  • Bestor TH . 2000 Hum. Mol. Genet. 9: 2395–2402

  • Bird A . 2001 Science 294: 2113–2115

  • Bird A . 2002 Genes. Dev. 16: 6–21

  • Bird AP, Wolffe AP . 1999 Cell 99: 451–454

  • Bonfils C, Beaulieu N, Chan E, Cotton-Montpetit J, MacLeod AR . 2000 J. Biol. Chem. 275: 10754–10760

  • Bourc'his D, Xu G-L, Lin C-S, Bollman B, Bestor TH . 2001 Science 294: 2536–2539

  • Brehm A, Langst G, Kehle J, Clapier CR, Imhof A, Eberharter A, Muller J, Becker PB . 2000 EMBO J. 19: 4332–4341

  • Brehm AB, Miska EA, McCance DJ, Reid JL, Bannister AJ, Kouzarides T . 1998 Nature 391: 597–601

  • Cameron EE, Bachman KE, Myohanen S, Herman JG, Baylin SB . 1999 Nature Genet. 21: 103–107

  • Cardoso MC, Leonhardt H . 1999 J. Cell Biol. 147: 25–32

  • Carlson LL, Page AW, Bestor TH . 1992 Genes. Dev. 6: 2536–2541

  • Clapier CR, Langst G, Corona DFV, Becker PB, Nightingale KP . 2001 Mol. Cell. Biol. 21: 875–883

  • Clapier CR, Nightingale KP, Becker PB . 2002 Nucleic Acids Res. 30: 649–655

  • Corona DFV, Clapier CR, Becker PB, Tamkun JW . 2002 EMBO Rep. 3: 242–247

  • Csankovszki G, Nagy A, Jaenisch R . 2001 J. Cell Biol. 153: 773–783

  • Dennis K, Fan T, Geiman T, Yan Q, Muegge K . 2001 Genes. Dev. 15: 2940–2944

  • Deuring R, Fanti L, Armstrong JA, Sarte M, Papoulas O, Prestel M, Daubresse G, Verardo M, Moseley SL, Berloco M, Tsukiyama T, Wu C, Pimpinelli S, Tamkun JW . 2000 Cell 5: 355–365

  • Di Croce L, Raker AA, Corsaro M, Fazi F, Fanelli M, Faretta M, Fuks F, Coco FL, Kouzarides T, Nervi C, Minucci S, Pelicci PG . 2002 Science 295: 1079–1082

  • Doherty AS, Bartolomei MS, Schultz RM . 2002 Dev. Biol. 242: 255–266

  • Dong A, Yoder JA, Zhang X, Zhou L, Bestor TH, Cheng X . 2001 Nucleic Acids Res. 29: 439–448

  • Dyson N . 1998 Genes. Dev. 12: 2245–2262

  • Eden S, Hashimshony T, Keshet I, Cedar H, Thorne AW . 1998 Nature 394: 842

  • Ehrlich M, Buchanan KL, Tsein F, Jiang G, Sun B, Uicker W, Weemaes CMR, Smeets D, Sperling K, Belohradsky BH, Tommerup N, Misek DE, Rouillard J-M, Kuick R, Hanash SM . 2001 Hum. Mol. Genet. 10: 2917–2931

  • Eisen JA, Sweder KS, Hanawalt PC . 1995 Nucleic Acids Res. 23: 2715–2723

  • Ellis NA . 1997 Curr. Opin. Genet. Dev. 7: 354–363

  • Fan G, Beard C, Chen RZ, Csankovszki G, Sun Y, Siniaia M, Biniszkiewicz D, Bates B, Lee PP, Kuhn R, Trumpp A, Poon C-S, Wilson CB, Jaenisch R . 2001 J. Neurosci. 21: 788–797

  • Feng Q, Zhang Y . 2001 Genes. Dev. 15: 827–832

  • Finnegan EJ, Peacock WJ, Dennis ES . 1996 Proc. Natl. Acad. Sci. USA 93: 8449–8454

  • Flynn J, Glickman JF, Reich NO . 1996 Biochemistry 35: 7308–7315

  • Franceschini P, Martino S, Ciocchini M, Ciuti E, Vardeu MP, Guala A, Signorile F, Camerano P, Franceschini D, Tovo PA . 1995 Eur. J. Pediatr. 154: 840–846

  • Fuks F, Bergers WA, Brehm A, Hughes-Davies L, Kouzarides T . 2000 Nature Genet. 24: 88–91

  • Fuks F, Burgers WA, Godin N, Kasai M, Kouzarides T . 2001 EMBO J. 20: 2536–2544

  • Geiman TM, Muegge K . 2000 Proc. Natl. Acad. Sci. USA 97: 4772–4777

  • Gibbons RJ, Bachoo S, Picketts DJ, Aftimos S, Asenbauer B, Bergoffen J, Berry SA, Dahl N, Fryer A, Keppler K, Kurosawa K, Levin ML, Masuno M, Neri G, Pierpont ME, Slaney SF, Higgs DR . 1997 Nature Genet 17: 146–148

  • Gibbons RJ, McDowell TL, Raman S, O'Rourke DM, Garrick D, Ayyub H, Higgs DR . 2000 Nature Genet. 24: 368–371

  • Glickman JF, Pavlovich JG, Reich NO . 1997 J. Biol. Chem. 272: 17851–17857

  • Gowher H, Jeltsch A . 2001 J. Mol. Biol. 309: 1201–1208

  • Hamiche A, Kang J-G, Dennis C, Xiao H, Wu C . 2001 Proc. Natl. Acad. Sci. USA 98: 14316–14321

  • Hansen RS, Stoger R, Wijmenga C, Stanek AM, Canfield TK, Luo P, Matarazzo MR, D'Esposito M, Feil R, Gimelli G, Weemaes CMR, Laird CD, Gartler SM . 2000 Hum. Mol. Genet. 9: 2575–2587

  • Hansen RS, Wijmenga C, Luo P, Stanek AM, Canfield TK, Weemaes CMR, Gartler SM . 1999 Proc. Natl. Acad. Sci. USA 96: 14412–14417

  • Hassan KMA, Norwood T, Gimelli G, Gartler SM, Hansen RS . 2001 Hum. Mol. Genet. 109: 452–462

  • Havas K, Whitehouse I, Owen-Hughes T . 2001 Cell. Mol. Life Sci. 58: 673–682

  • Heard E, Rougeulle C, Arnaud D, Avner P, Allis CD, Spector DL . 2001 Cell 107: 727–738

  • Howell CY, Bestor TH, Ding F, Latham KE, Mertineit C, Trasler JM, Trasler JM, Chaillet JR . 2001 Cell 104: 829–838

  • Hsieh C-L . 1999 Mol. Cell. Biol. 19: 8211–8218

  • Hsu D-W, Lin M-J, Lee T-L, Wen S-C, Chen X, Shen C-KJ . 1999 Proc. Natl. Acad. Sci. USA 96: 9751–9756

  • Hung M-S, Karthikeyan N, Huang B, Koo H-C, Kiger J, Shen C-KJ . 1999 Proc. Natl. Acad. Sci. USA 96: 11940–11945

  • Ito T, Levenstein ME, Fyodorov DV, Kutach AK, Kobayashi R, Kadonaga JT . 1999 Genes. Dev. 13: 1529–1539

  • Jackson JP, Lindroth AM, Cao X, Jacobsen SE . 2002 Nature advance online publication 17 March

  • Jackson-Grusby L, Beard C, Possemato R, Tudor M, Fambrough D, Csankovzki G, Dausman J, Lee P, Wilson C, Lander E, Jaenisch R . 2001 Nature Genet. 27: 31–39

  • Jarvis CD, Geiman T, Vila-Storm MP, Osipovich O, Akella U, Candeias S, Nathan I, Durum SK, Muegge K . 1996 Gene 169: 203–207

  • Jeanpierre M, Turleau C, Aurias A, Prieur M, Ledeist F, Fischer A, Viegas-Pequignot E . 1993 Hum. Mol. Genet. 2: 731–735

  • Jeddeloh JA, Stokes TL, Richards EJ . 1999 Nature Genet. 22: 94–97

  • Jenuwein T, Allis CD . 2001 Science 293: 1074–1080

  • Jones PA, Laird PW . 1999 Nature Genet. 21: 163–166

  • Kal AJ, Mahmoudi T, Zak NB, Verrijzer CP . 2000 Genes Dev. 14: 1058–1071

  • Kennedy BK, Barbie DA, Classon M, Dyson N, Harlow E . 2000 Genes Dev. 14: 2855–2868

  • Kondo T, Bobek MP, Kuick R, Lamb B, Zhu X, Narayan A, Bourc'his D, Viegas-Pequignot E, Ehrlich M, Hanash SM . 2000 Hum. Mol. Genet. 9: 597–604

  • Lei H, Oh SP, Okano M, Juttermann R, Goss KA, Jaenisch R, Li E . 1996 Development 122: 3195–3205

  • Leonhardt H, Page AW, Weier H, Bestor TH . 1992 Cell 71: 865–873

  • LeRoy G, Loyola A, Lane WS, Reinberg D . 2000 J. Biol. Chem. 275: 14787–14790

  • Li E, Beard C, Jaenisch R . 1993 Nature 366: 362–365

  • Li E, Bestor TH, Jaenisch R . 1992 Cell 69: 915–926

  • Li H, Leo C, Zhu J, Wu X, O'Neil J, Park E-J, Chen JD . 2000 Mol. Cell. Biol. 20: 1784–1796

  • Lin M-J, Lee T-L, Hsu D-W, Shen C-KJ . 2000 FEBS Lett. 469: 101–104

  • Liu Y, Oakeley EJ, Sun L, Jost J-P . 1998 Nucleic Acids Res. 26: 1038–1045

  • Luo RX, Postigo AA, Dean DC . 1998 Cell 92: 463–473

  • Lyko F, Ramsahoye BH, Kashevsky H, Tudor M, Mastrangelo M-A, Orr-Weaver TL, Jaenisch R . 1999 Nature Genet. 23: 363–366

  • Lyko F, Whittaker AJ, Orr-Weaver TL, Jaenisch R . 2000 Mech. Dev. 95: 215–217

  • Martienssen R, Henikoff S . 1999 Nature Genet. 22: 6–7

  • Meng G, Inazawa J, Ishida R, Tokura K, Nakahara K, Aoki K, Kasai M . 2000 Gene 242: 59–64

  • Mertineit C, Yoder JA, Taketo T, Laird DW, Trasler JM, Bestor TH . 1998 Development 125: 889–897

  • Michaelson JS, Bader D, Kuo F, Kozak C, Leder P . 1999 Genes. Dev. 13: 1918–1923

  • Miniou P, Jeanpierre M, Bourc'his D, Barbosa ACC, Blanquet V, Viegas-Pequignot E . 1997 Hum. Genet. 99: 738–745

  • Miura A, Yonebayashi S, Watanabe K, Toyama T, Shimada H, Kakutani T . 2001 Nature 411: 212–214

  • Muller S, Hoege C, Pyrowolakis G, Jentsch S . 2001 Nature Rev. Mol. Cell Biol. 2: 202–210

  • Nielsen SJ, Schneider R, Bauer U-M, Bannister AJ, Morrison A, O'Carroll D, Firestein R, Cleary M, Jenuwein T, Herrera RE, Kouzarides T . 2001 Nature 412: 561–565

  • Okano M, Bell DW, Haber DA, Li E . 1999 Cell 99: 247–257

  • Okano M, Xie S, Li E . 1998a Nature Genet. 19: 219–220

  • Okano M, Xie S, Li E . 1998b Nucleic Acids Res. 26: 2536–2540

  • Pannell D, Osborne CS, Yao S, Sukonnik T, Pasceri P, Karaiskakis A, Okano M, Li E, Lipshitz HD, Ellis J . 2000 EMBO J. 19: 5884–5894

  • Poot RA, Dellaire G, Hulsmann BB, Grimaldi MA, Corona DFV, Becker PB, Bickmore WA, Varga-Weisz PD . 2000 EMBO J. 19: 3377–3387

  • Pradhan S, Bacolla A, Wells RD, Roberts RJ . 1999 J. Biol. Chem. 274: 33002–33010

  • Pradhan S, Kim G-D . 2002 EMBO J. 21: 779–788

  • Pradhan S, Talbot D, Sha M, Benner J, Hornstra L, Li E, Jaenisch R, Roberts RJ . 1997 Nucleic Acids Res. 25: 4666–4673

  • Qiu C, Sawada K, Zhang X, Cheng X . 2002 Nature Struct. Biol. 9: 217–224

  • Raabe EH, Abdurrahman L, Behbehani G, Areci RJ . 2001 Dev. Dyn. 221: 92–105

  • Rea S, Eisenhaber F, O'Caroll D, Strahl BD, Sun Z-W, Schmid M, Opravil S, Mechtler K, Ponting CP, Allis CD, Jenuwein T . 2000 Nature 406: 593–599

  • Reik W, Dean W, Walter J . 2001 Science 293: 1089–1093

  • Rhee I, Jair K-W, Yen R-WC, Lengauer C, Herman JG, Kinzler KW, Vogelstein B, Baylin SB, Schuebel KE . 2000 Nature 404: 1003–1007

  • Robertson KD . 2001 Oncogene 20: 3139–3155

  • Robertson KD, Ait-Si-Ali S, Yokochi T, Wade PA, Jones PL, Wolffe AP . 2000a Nature Genet. 25: 338–342

  • Robertson KD, Keyomarsi K, Gonzales FA, Velicescu M, Jones PA . 2000b Nucleic Acids Res. 28: 2108–2113

  • Robertson KD, Uzvolgyi E, Liang G, Talmadge C, Sumegi J, Gonzales FA, Jones PA . 1999 Nucleic Acids Res. 27: 2291–2298

  • Robertson KD, Wolffe AP . 2000 Nature Rev. Genet. 1: 11–19

  • Rountree MR, Bachman KE, Baylin SB . 2000 Nature Genet. 25: 269–277

  • Ryan RF, Schultz DC, Ayyanathan K, Singh PB, Friedman JR, Fredericks WJ, Rasucher FR . 1999 Mol. Cell. Biol. 19: 4366–4378

  • Schuffenhauer S, Bartsch O, Stumm M, Buchholz T, Petropoulou T, Kraft S, Belohradsky B, Hinkel GK, Meitinger T, Wegner R-D . 1995 Hum. Genet. 96: 562–571

  • Smeets DFCM, Moog U, Weemaes CMR, Vaes-Peeters G, Merkx GFM, Niehof JP, Hamers G . 1994 Hum. Genet. 94: 240–246

  • Tagarro I, Fernandez-Peralta AM, Gonzales-Aguilera JJ . 1994 Hum. Genet. 93: 383–388

  • Tamaru H, Selker EU . 2001 Nature 414: 277–283

  • Tatematsu K-i, Yamazaki T, Ishikawa F . 2000 Genes Cells 5: 677–688

  • The Arabidopsis Genome Initiative. 2000 Nature 408: 796–815

  • Tong JK, Hassig CA, Schnitzler GR, Kingston RE, Schreiber SL . 1998 Nature 395: 917–921

  • Tran HG, Steger DJ, Iyer VR, Johnson AD . 2000 EMBO J. 19: 2323–2331

  • Tucker KL . 2001 Neuron 30: 649–652

  • Tuck-Muller CM, Narayan A, Tsien F, Smeets DFCM, Sawyer J, Fiala ES, Sohn OS, Ehrlich M . 2000 Cytogenet. Cell Genet. 89: 121–128

  • Varga-Weisz P . 2001 Oncogene 20: 3076–3085

  • Vielle-Calzada J-P, Thomas J, Spillane C, Coluccio A, Hoeppner MA, Grossniklaus U . 1999 Genes Dev. 13: 2971–2982

  • Vignali M, Hassan AH, Neely KE, Workman JL . 2000 Mol. Cell. Biol. 20: 1899–1910

  • Wade PA, Gegonne A, Jones PL, Ballestar E, Aubry F, Wolffe AP . 1999 Nature Genet. 23: 62–66

  • Walsh CP, Chaillet JR, Bestor TH . 1998 Nature Genet. 20: 116–117

  • Wang W, Cote J, Xue Y, Zhou S, Khavari PA, Biggar SR, Muchardt C, Kalpana GV, Goff SP, Yaniv M, Workman JL, Crabtree GR . 1996 EMBO J. 15: 5370–5382

  • Whitehouse I, Flaus A, Cairns BR, White MF, Workman JL, Owen-Hughes T . 1999 Nature 400: 784–787

  • Wilkinson CRM, Bartlett R, Nurse P, Bird AP . 1995 Nucleic Acids Res. 23: 1995

  • Wolffe AP, Pruss D . 1996 Cell 84: 817–819

  • Xie S, Wang Z, Okano M, Nogami M, Li Y, He W-W, Okumura K, Li E . 1999 Gene 236: 87–95

  • Xu G-L, Bestor TH, Bourc'his D, Hsieh C-L, Tommerup N, Bugge M, Hulten M, Qu Russo JJ, Viegas-Pequignot E . 1999 Nature 402: 187–191

  • Yen R-WC, Vertino PM, Nelkin BD, Yu JJ, El-Deiry W, Cumaraswamy A, Lennon GG, Trask BJ, Celano P, Baylin SB . 1992 Nucleic Acids Res. 20: 2287–2291

  • Yoder JA, Bestor TH . 1998 Hum. Mol. Genet. 7: 279–284

  • Yoder JA, Walsh CP, Bestor TH . 1997 Trends Genet. 13: 335–340

  • Yokochi T, Robertson KD . 2002 J. Biol. Chem. 277: 11735–11745

  • Zhong S, Salomoni P, Pandolfi PP . 2000a Nature Cell Biol. 2: E85–E90

  • Zhong S, Salomoni P, Ronchetti S, Guo A, Ruggero D, Pandolfi PP . 2000b J. Exp. Med. 191: 631–639

Download references

Acknowledgements

KD Robertson is a Cancer Scholar supported by the National Cancer Institute (NIH grant CA84535-01). I thank Andrea Kahler Robertson for critical reading of the manuscript. This article is dedicated to my former mentor and friend, Alan Wolffe, who died tragically last year.

Author information

Authors and Affiliations

  1. Epigenetic Gene Regulation and Cancer Section, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, Maryland, USA

    Keith D Robertson

Authors
  1. Keith D Robertson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Keith D Robertson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Robertson, K. DNA methylation and chromatin – unraveling the tangled web. Oncogene 21, 5361–5379 (2002). https://doi.org/10.1038/sj.onc.1205609

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205609

Keywords

This article is cited by

Search

Advanced search

Quick links