Abstract
Cancer is a process driven by the accumulation of abnormalities in gene function. While many of these changes are genetic, epigenetically mediated changes in gene expression are being increasingly appreciated. This latter process emphasizes the need to understand two key components of heritable, but reversible, modulation of gene promoter function that are closely tied to one another – formation of chromatin which modulates transcription and establishing patterns of DNA methylation. The link lies first in the recruitment to methylated cytosines of a family of methyl-CpG binding domain proteins (MBDs), which are direct transcriptional repressors and can complex with transcriptional corepressors including histone deacetylases (HDACs). Additionally, the proteins that catalyze DNA methylation, DNA methyltransferases (DNMTs), also directly repress transcription and associate with HDACs. Regulation of these above chromatin-DNA methylation interactions as a function of DNA replication timing is emerging as a key event in the inheritance of transcriptionally repressed domains of the genome. Importantly, synergy between HDAC activity and DNA methylation is operative for a key epigenetic abnormality in cancer cells, transcriptional silencing of tumor suppressor genes. This change has now been recognized for genes that are essential for normal regulation of virtually every major cell function including cell growth, differentiation, apoptosis, DNA repair, and cell–cell, cell–substratum interaction. Understanding the molecular determinants of both normal and abnormal patterns of chromatin formation and DNA methylation thus holds great promise for our understanding of cancer and for means to better diagnose, prevent, and treat this disease.
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References
Aguirre-Arteta AM, Grunewald I, Cardoso MC, Leonhardt H . 2000 Cell Growth Differ. 11: 551–559
Amiel A, Kirgner I, Gaber E, Manor Y, Fejgin M, Lishner M . 1999 Cancer Genet. Cytogenet. 108: 32–37
Amiel A, Kolodizner T, Fishman A, Gaber E, Klein Z, Beyth Y, Fejgin MD . 1998b Cancer 83: 1966–1971
Amiel A, Litmanovitch T, Lishner M, Mor A, Gaber E, Tangi I, Fejgin M, Avivi L . 1998a Genes Chromosomes. Cancer 22: 225–231
Annunziato AT, Seale RL . 1983 J. Biol. Chem. 258: 12675–12684
Bakin AV, Curran T . 1999 Science 283: 387–390
Baylin SB, Herman JG . 2000 Epigenetics and Loss of Gene Function in Cancer In DNA Alterations in Cancer, Melanie Erlich, (ed) Natick, MA: Eaton Publishing pp. 293–309
Baylin SB, Herman JG, Graff JR, Vertino PM, Issa JP . 1998 Adv. Cancer Res. 72: 141–196
Belinsky SA, Nikula KJ, Baylin SB, Issa JP . 1996 Proc. Natl. Acad. Sci. USA 93: 4045–4050
Bestor TH . 1992 EMBO J. 11: 2611–2617
Bestor TH . 2000 Hum. Mol. Genet. 9: 2395–2402
Bianco T, Chenevix-Trench G, Walsh DC, Cooper JE, Dobrovic A . 2000 Carcinogenesis 21: 147–151
Bird A . 1992 Cell 70: 5–8
Bird AP . 1980 Nucleic Acids Res. 8: 1499–1504
Bird AP . 1995 Trends. Genet. 11: 94–100
Bird AP, Wolffe AP . 1999 Cell 99: 451–454
Brandeis M, Ariel M, Cedar H . 1993 Bioessays 15: 709–713
Brandeis M, Frank D, Keshet I, Siegfried Z, Mendelsohn M, Nemes A, Temper V, Razin A, Cedar H . 1994 Nature 371: 435–438
Buschhausen G, Wittig B, Graessmann M, Graessmann A . 1987 Proc. Natl. Acad. Sci. USA 84: 1177–1181
Cameron EE, Bachman KE, Myohanen S, Herman JG, Baylin SB . 1999 Nat. Genet. 21: 103–107
Chen RZ, Pettersson U, Beard C, Jackson-Grusby L, Jaenisch R . 1998 Nature 395: 89–93
Cheng NC, Beitsma M, Chan A, Op DC, Westerveld A, Pronk J, Versteeg R . 1996a Oncogene 13: 1737–1744
Cheng NC, Chan AJ, Beitsma MM, Speleman F, Westerveld A, Versteeg R . 1996b Hum. Mol. Genet. 5: 309–317
Chuang LS, Ian HI, Koh TW, Ng HH, Xu G, Li BF . 1997 Science 277: 1996–2000
Colot V, Maloisel L, Rossignol JL . 1996 Cell 86: 855–864
Colot V, Rossignol JL . 1999 Bioessays 21: 402–411
Conway KE, McConnell BB, Bowring CE, Donald CD, Warren ST, Vertino PM . 2000 Cancer Res. 60: 6236–6242
Cross SH, Meehan RR, Nan X, Bird A . 1997 Nat. Genet. 16: 256–259
Dammann R, Li C, Yoon JH, Chin PL, Bates S, Pfeifer GP . 2000 Nat. Genet. 25: 315–319
Eads CA, Danenberg KD, Kawakami K, Saltz LB, Danenberg PV, Laird PW . 1999 Cancer Res. 59: 2302–2306
Eden S, Cedar H . 1994 Curr. Opin. Genet. Dev. 4: 255–259
Enver T, Zhang JW, Papayannopoulou T, Stamatoyannopoulos G . 1988 Genes Dev. 2: 698–706
Esteller M, Avizienyte E, Corn PG, Lothe RA, Baylin SB, Aaltonen LA, Herman JG . 2000d Oncogene 19: 164–168
Esteller M, Silva JM, Dominguez G, Bonilla F, Matias-Guiu X, Lerma E, Bussaglia E, Prat J, Harkes IC, Repasky EA, Gabrielson E, Schutte M, Baylin SB, Herman JG . 2000c J. Natl. Cancer Inst. 92: 564–569
Esteller M, Sparks A, Toyota M, Sanchez-Cespedes M, Capella G, Peinado MA, Gonzalez S, Tarafa G, Sidransky D, Meltzer SJ, Baylin SB, Herman JG . 2000b Cancer Res. 60: 4366–4371
Esteller M, Tortola S, Toyota M, Capella G, Peinado MA, Baylin SB, Herman JG . 2000a Cancer Res. 60: 129–133
Florl AR, Lower R, Schmitz-Drager BJ, Schulz WA . 1999 Br. J. Cancer 80: 1312–1321
Fuks F, Burgers WA, Brehm A, Hughes-Davies L, Kouzarides T . 2000 Nat. Genet. 24: 88–91
Gaudet F, Talbot D, Leonhardt H, Jaenisch R . 1998 J. Biol. Chem. 273: 32725–32729
Gowher H, Leismann O, Jeltsch A . 2000 EMBO J. 19: 6918–6923
Graff JR, Herman JG, Lapidus RG, Chopra H, Xu R, Jarrard DF, Isaacs WB, Pitha PM, Davidson NE, Baylin SB . 1995 Cancer Res. 55: 5195–5199
Grunstein M . 1997 Nature 389: 349–352
Hansen RS, Wijmenga C, Luo P, Stanek AM, Canfield TK, Weemaes CM, Gartler SM . 1999 Proc. Natl. Acad. Sci. USA 96: 14412–14417
Harbour JW, Dean DC . 2000a Curr. Opin. Cell Biol. 12: 685–689
Harbour JW, Dean DC . 2000b The Rb/E2F pathway: expanding roles and emerging paradigms Genes Dev. 14: 2393–2409
Hendrich B, Bird A . 1998 Mol. Cell Biol. 18: 6538–6547
Herman JG . 1999 Semin. Cancer Biol. 9: 359–367
Hernandez R, Frady A, Zhang XY, Varela M, Ehrlich M . 1997 Cytogenet. Cell Genet. 76: 196–201
Hung MS, Karthikeyan N, Huang B, Koo HC, Kiger J, Shen CJ . 1999 Proc. Natl. Acad. Sci. USA 96: 11940–11945
Ji W, Hernandez R, Zhang XY, Qu GZ, Frady A, Varela M, Ehrlich M . 1997 Mutat. Res. 379: 33–41
Jones PL, Veenstra GJ, Wade PA, Vermaak D, Kass SU, Landsberger N, Strouboulis J, Wolffe AP . 1998 Nat. Genet. 19: 187–191
Kass SU, Landsberger N, Wolffe AP . 1997 Curr. Biol. 7: 157–165
Kass SU, Wolffe AP . 1996 Histones, histone modifications, and the inheritance of chromatin structure In Epigenetic Mechanisms of Gene Regulation, Russo V.E.A., Martienssen R.A. and Riggs A.D. (eds) New York: Cold Spring Harbor Laboratory Press pp. 529–546
Kennedy BK, Barbie DA, Classon M, Dyson N, Harlow E . 2000 Genes Dev. 14: 2855–2868
Keshet I, Lieman-Hurwitz J, Cedar H . 1986 Cell 44: 535–543
Knox JD, Araujo FD, Bigey P, Slack AD, Price GB, Zannis-Hadjopoulos M, Szyf M . 2000 J. Biol. Chem. 275: 17986–17990
Krude T . 1999 Curr. Biol. 9: 394–396
Laird PW, Jaenisch R . 1996 Annu. Rev. Genet. 30: 441–464
Leonhardt H, Page AW, Weier HU, Bestor TH . 1992 Cell 71: 865–873
Leonhardt H, Rahn HP, Weinzierl P, Sporbert A, Cremer T, Zink D, Cardoso MC . 2000 J. Cell Biol. 149: 271–280
Lewis JD, Meehan RR, Henzel WJ, Maurer-Fogy I, Jeppesen P, Klein F, Bird A . 1992 Cell 69: 905–914
Li E, Bestor TH, Jaenisch R . 1992 Cell 69: 915–926
Liu Y, Oakeley EJ, Sun L, Jost JP . 1998 Nucleic. Acids. Res. 26: 1038–1045
Lock LF, Takagi N, Martin GR . 1987 Cell 48: 39–46
Lyko F, Ramsahoye BH, Jaenisch R . 2000b Nature 408: 538–540
Lyko F, Whittaker AJ, Orr-Weaver TL, Jaenisch R . 2000a Mech. Dev. 95: 215–217
MacLeod AR, Szyf M . 1995 J. Biol. Chem. 270: 8037–8043
Macleod D, Charlton J, Mullins J, Bird AP . 1994 Genes Dev. 8: 2282–2292
Meehan RR, Lewis JD, McKay S, Kleiner EL, Bird AP . 1989 Cell 58: 499–507
Mertineit C, Yoder JA, Taketo T, Laird DW, Trasler JM, Bestor TH . 1998 Development 125: 889–897
Mummaneni P, Walker KA, Bishop PL, Turker MS . 1995 J. Biol. Chem. 270: 788–792
Mummaneni P, Yates P, Simpson J, Rose J, Turker MS . 1998 Nucleic. Acids. Res. 26: 5163–5169
Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, Eisenman RN, Bird A . 1998 Nature 393: 386–389
Narayan A, Ji W, Zhang XY, Marrogi A, Graff JR, Baylin SB, Ehrlich M . 1998 Int. J. Cancer 77: 833–838
Nass SJ, Ferguson AT, El Ashry D, Nelson WG, Davidson NE . 1999 Oncogene 18: 7453–7461
Ng HH, Jeppesen P, Bird A . 2000 Mol. Cell Biol. 20: 1394–1406
Ng HH, Zhang Y, Hendrich B, Johnson CA, Turner BM, Erdjument-Bromage H, Tempst P, Reinberg D, Bird A . 1999 Nat. Genet. 23: 58–61
Okano M, Bell DW, Haber DA, Li E . 1999 Cell 99: 247–257
Pradhan S, Bacolla A, Wells RD, Roberts RJ . 1999 J. Biol. Chem. 274: 33002–33010
Pradhan S, Talbot D, Sha M, Benner J, Hornstra L, Li E, Jaenisch R, Roberts RJ . 1997 Nucleic. Acids. Res. 25: 4666–4673
Qu G, Dubeau L, Narayan A, Yu MC, Ehrlich M . 1999 Mutat. Res. 423: 91–101
Ramchandani S, MacLeod AR, Pinard M, von Hofe E, Szyf M . 1997 Proc. Natl. Acad. Sci. USA 94: 684–689
Rhee I, Jair KW, Yen RW, Lengauer C, Herman JG, Kinzler KW, Vogelstein B, Baylin SB, Schuebel KE . 2000 Nature 404: 1003–1007
Robertson KD, Ait SA, Yokochi T, Wade PA, Jones PL, Wolffe AP . 2000 Nat. Genet. 25: 338–342
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 Nat. Rev. Genet. 1: 11–19
Roder K, Hung MS, Lee TL, Lin TY, Xiao H, Isobe KI, Juang JL, Shen CJ . 2000 Mol. Cell Biol. 20: 7401–7409
Rountree MR, Bachman KE, Baylin SB . 2000 Nat. Genet. 25: 269–277
Sado T, Fenner MH, Tan SS, Tam P, Shioda T, Li E . 2000 Dev. Biol. 225: 294–303
Shibahara K, Stillman B . 1999 Cell 96: 575–585
Sobel RE, Cook RG, Perry CA, Annunziato AT, Allis CD . 1995 Proc. Natl. Acad. Sci. USA 92: 1237–1241
Tate PH, Bird AP . 1993 Curr. Opin. Genet. Dev. 3: 226–231
Teitz T, Wei T, Valentine MB, Vanin EF, Grenet J, Valentine VA, Behm FG, Look AT, Lahti JM, Kidd VJ . 2000 Nat. Med. 6: 529–535
Tuck-Muller CM, Narayan A, Tsien F, Smeets DF, Sawyer J, Fiala ES, Sohn OS, Ehrlich M . 2000 Cytogenet. Cell Genet. 89: 121–128
Tweedie S, Ng HH, Barlow AL, Turner BM, Hendrich B, Bird A . 1999 Nat. Genet. 23: 389–390
Vertino PM, Yen RW, Gao J, Baylin SB . 1996 Mol. Cell Biol. 16: 4555–4565
Wade PA, Gegonne A, Jones PL, Ballestar E, Aubry F, Wolffe AP . 1999 Nat. Genet. 23: 62–66
Walsh CP, Chaillet JR, Bestor TH . 1998 Nat. Genet. 20: 116–117
Wu J, Issa JP, Herman J, Bassett DEJ, Nelkin BD, Baylin SB . 1993 Proc. Natl. Acad. Sci. USA 90: 8891–8895
Xie S, Wang Z, Okano M, Nogami M, Li Y, He WW, Okumura K, Li E . 1999 Gene 236: 87–95
Xu GL, Bestor TH, Bourchis D, Hsieh CL, Tommerup N, Bugge M, Hulten M, Qu X, Russo JJ, Viegas-Pequignot E . 1999 Nature 402: 187–191
Yoder JA, Soman NS, Verdine GL, Bestor TH . 1997b J. Mol. Biol. 270: 385–395
Yoder JA, Walsh CP, Bestor TH . 1997a Trends. Genet. 13: 335–340
Yoder JA, Yen RC, Vertino PM, Bestor TH, Baylin SB . 1996 J. Biol. Chem. 271: 31092–31097
Zhang Y, Ng HH, Erdjument-Bromage H, Tempst P, Bird A, Reinberg D . 1999 Genes. Dev. 13: 1924–1935
Zhang Z, Shibahara K, Stillman B . 2000 Nature 408: 221–225
Zheng S, Chen P, McMillan A, Lafuente A, Lafuente MJ, Ballesta A, Trias M, Wiencke JK . 2000 Carcinogenesis 21: 2057–2064
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Rountree, M., Bachman, K., Herman, J. et al. DNA methylation, chromatin inheritance, and cancer. Oncogene 20, 3156–3165 (2001). https://doi.org/10.1038/sj.onc.1204339
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