Epigenetic regulation of gene expression: How the genome integrates intrinsic and environmental signals

Nature Genetics

Volumn 33, Issue 3S, 2003, Pages 245-254

  Jaenisch, Rudolf ^a   Bird, Adrian ^b  

^a WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH   (United States)

^b UNIVERSITY OF EDINBURGH   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

DNA; HISTONE;

CANCER; DIET; DNA METHYLATION; ENVIRONMENTAL FACTOR; EPIGENETICS; GENE ACTIVATION; GENE EXPRESSION; GENE EXPRESSION REGULATION; GENE IDENTIFICATION; GENETIC ANALYSIS; GENOMICS; HEREDITY; HUMAN; MITOSIS; MOLECULAR MECHANICS; MUTATION; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; REVIEW;

AGING; ANIMALS; CLONING, ORGANISM; DIET; DNA METHYLATION; DOSAGE COMPENSATION, GENETIC; GENE EXPRESSION REGULATION, DEVELOPMENTAL; GENETIC DISEASES, INBORN; GENOME; GENOMIC IMPRINTING; HUMANS; MICE; MODELS, GENETIC; MUTATION; NEOPLASMS; PHENOTYPE; SIGNAL TRANSDUCTION;

ANIMALIA; EUKARYOTA;

EID: 0037372003     PISSN: 10614036     EISSN: 15461718     Source Type: Journal    
DOI: 10.1038/ng1089     Document Type: Review

References (186)

1. Waddington, C. The genetic control of wing development in Drosophila. J. Genet. 41, 75-80 (1940).
2. Issa, J.P. CpG-island methylation in aging and cancer. Curr. Top. Microbiol. Immunol. 249, 101-118 (2000).
3. Jahner, D. et al. De novo methylation and expression of retroviral genomes during mouse embryogenesis. Nature 298, 623-628 (1982).
4. Riggs, A.D. X inactivation, differentiation, and DNA methylation. Cytogenet. Cell Genet. 14, 9-25 (1975).
5. Holliday, R and Pugh, J.E. DNA modification mechanisms and gene activity during development. Science 187, 226-232 (1975).
6. Wolffe, A.P and Matzke, M.A. Epigenetics: Regulation through repression. Science 286, 481-486 (1999).
7. Urnov, F.D and Wolffe, A.P. Above and within the genome: Epigenetics past and present. J. Mammary Gland Biol. Neoplasia 6, 153-167 (2001).
8. Jones, P.A and Takai, D. The role of DNA methylation in mammalian epigenetics. Science 293, 1068-1070 (2001).
9. Ferguson-Smith, A.C and Surani, M.A. Imprinting and the epigenetic asymmetry between parental genomes. Science 293, 1086-1089 (2001).
10. Reik, W and Walter, J. Genomic imprinting: Parental influence on the genome. Nat. Rev. Genet. 2, 21-32 (2001).
11. Bird, A. DNA methylation patterns and epigenetic memory. Genes Dev. 16, 6-21 (2002).
12. Li, E. Chromatin modification and epigenetic reprogramming in mammalian development. Nat. Rev. Genet. 3, 662-673 (2002).
13. Jaenisch, R. DNA methylation and imprinting: Why bother? Trends Genet. 13, 323-329 (1997).
14. Mayer, W., Niveleau, A., Walter, J., Fundele, R and Haaf, T. Demethylation of the zygotic paternal genome. Nature 403, 501-502 (2000).
15. Oswald, J. et al. Active demethylation of the paternal genome in the mouse zygote. Curr. Biol. 10, 475-478 (2000).
16. Ehrlich, M. et al. Amount and distribution of 5-methylcytosine in human DNA from different types of tissues of cells. Nucleic Acids Res. 10, 2709-2721 (1982).
17. Jones, P. et al. De novo methylation of the MyoD1 CpG island during the estab-lisment of immortal cell lines. Proc. Natl. Acad. Sci. USA 87, 6117-6121 (1990).
18. Kawai, J. et al. Comparison of DNA methylation patterns among mouse cell lines by restriction landmark genomic scanning. Mol. Cell. Biol. 14, 7421-7427 (1994).
19. Bestor, T.H. The DNA methyltransferases of mammals. Hum. Mol. Genet. 9, 2395-2402 (2000).
20. Li, E., Bestor, T.H and Jaenisch, R. Targeted mutation of the DNA methyltrans-ferase gene results in embryonic lethality. Cell 69, 915-926 (1992).
21. Lei, H. et al. De novo DNA cytosine methyltransferase activities in mouse embryonic stem cells. Development 122, 3195-3205 (1996).
22. Stancheva, I and Meehan, R.R. Transient depletion of xDnmt1 leads to premature gene activation in Xenopus embryos. Genes Dev. 14, 313-327 (2000).
23. Howell, C. et al. Genomic imprinting disrupted by a maternal effect mutation in the Dnmt1 gene. Cell 104, 829-838 (2001).
24. Okano, M., Bell, D.W., Haber, D.A and Li, E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99, 247-257 (1999).
25. Lyko, F. et al. Mammalian (cytosine-5) methyltransferases cause genomic DNA methylation and lethality in Drosophila. Nat. Genet. 23, 363-366 (1999).
26. Bourc’his, D., Xu, G.L., Lin, C.S., Bollman, B and Bestor, T.H. Dnmt3L and the estab­lishment of maternal genomic imprints. Science 294, 2536-2539 (2001).
27. Hata, K., Okano, M., Lei, H and Li, E. Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice. Development 129, 1983-1993 (2002).
28. Okano, M., Xie, S and Li, E. Dnmt2 is not required for de novo and maintenance methylation of viral DNA in embryonic stem cells. Nucleic Acids Res. 26, 2536-2540 (1998).
29. Lyko, F., Ramsahoye, B.H and Jaenisch, R. DNA methylation in Drosophila melanogaster. Nature 408, 538-540 (2000).
30. Gowher, H., Leismann, O and Jeltsch, A. DNA of Drosophila melanogaster contains 5-methylcytosine. EMBO J. 19, 6918-6923 (2000).
31. Panning, B and Jaenisch, R. DNA hypomethylation can activate Xist expression and silence X-linked genes. Genes Dev. 10, 1991-2002 (1996).
32. Stancheva, I., Hensey, C and Meehan, R.R. Loss of the maintenance methyltrans-ferase, xDnmt1, induces apoptosis in Xenopus embryos. EMBO J. 20, 1963-1973 (2001).
33. Jackson-Grusby, L. et al. Loss of genomic methylation causes p53-dependent apoptosis and epigenetic deregulation. Nat. Genet. 27, 31-39 (2001).
34. Rhee, I. et al. DNMT1 and DNMT3b cooperate to silence genes in human cancer cells. Nature 416, 552-556 (2002).
35. Walsh, C.P., Chaillet, J.R and Bestor, T.H. Transcription of IAP endogenous retroviruses is constrained by cytosine methylation. Nat. Genet. 20, 116-117 (1998).
36. Fan, G. et al. DNA hypomethylation perturbs the function and survival of CNS neurons in postnatal animals. J. Neurosci. 21, 788-797 (2001).
37. Walsh, C.P and Bestor, T.H. Cytosine methylation and mammalian development. Genes Dev. 13, 26-34 (1999).
38. Bird, A. CpG islands as gene markers in the vertebrate nucleus. Trends Genet. 3, 342-346 (1987).
39. Bird, A.P. CpG-rich islands and the function of DNA methylation. Nature 321, 209-213 (1986).
40. Gardiner-Garden, M and Frommer, M. CpG islands in vertebrate genomes. J. Mol. Biol. 196, 261-282 (1987).
41. Larsen, F., Gundersen, G., Lopez, R and Prydz, H. CpG islands as gene markers in the human genome. Genomics 13, 1095-1107 (1992).
42. Macleod, D., Ali, R.R and Bird, A. An alternative promoter in the mouse major hisocompatibility complex class II I-AP gene: Implications for the origin of CpG islands. Mol. Cell. Biol. 18, 4433-4443 (1998).
43. Adachi, N and Lieber, M.R. Bidirectional gene organization: A common architectural feature of the human genome. Cell 109, 807-809 (2002).
44. Voo, K.S., Carlone, D.L., Jacobsen, B.M., Flodin, A and Skalnik, D.G. Cloning of a mammalian transcriptional activator that binds unmethylated CpG motifs and shares a CXXC domain with DNA methyltransferase, human trithorax, and methyl-CpG binding domain protein 1. Mol. Cell. Biol. 20, 2108-2121 (2000).
45. Lee, J.H., Voo, K.S and Skalnik, D.G. Identification and characterization of the DNA binding domain of CpG-binding protein. J. Biol. Chem. 276, 44669-44676 (2001).
46. Mohandas, T., Sparkes, R.S and Shapiro, L.J. Reactivation of an inactive human X chromosome: Evidence for X inactivation by DNA methylation. Science 211, 393-396 (1981).
47. Wolf, S.F., Jolly, D.J., Lunnen, K.D., Friedmann, T and Migeon, B.R. Methylation of the hypoxanthine phosphoribosyltransferase locus on the human X chromosome: Implications for X-chromosome inactivation. Proc. Natl. Acad. Sci. USA81, 2806-2810 (1984).
48. Riggs, A.D., Xiong, Z., Wang, L and LeBon, J.M. Methylation dynamics, epigenetic fidelity and X chromosome structure. Novartis Found. Symp. 214, 214-232 (1998).
49. Brandeis, M. et al. Sp1 elements protect a CpG island from de novo methylation. Nature 371, 435-438 (1994).
50. Macleod, D., Charlton, J., Mullins, J and Bird, A.P. Sp1 sites in the mouse aprt gene promoter are required to prevent methylation of the CpG island. Genes Dev. 8, 2282-2292 (1994).
51. Di Croce, L. et al. Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science 295, 1079-1082 (2002).
52. Santoro, R., Li, J and Grummt, I. The nucleolar remodeling complex NoRC mediates heterochromatin formation and silencing of ribosomal gene transcription. Nat. Genet. 32, 393-396 (2002).
53. Fuks, F., Burgers, W.A., Godin, N., Kasai, M and Kouzarides, T. Dnmt3a binds deacetylases and is recruited by a sequence-specific repressor to silence transcription. EMBO J. 20, 2536-2544 (2001).
54. Bachman, K.E., Rountree, M.R and Baylin, S.B. Dnmt3a and Dnmt3b are transcrip-tional repressors that exhibit unique localization properties to heterochromatin. J. Biol. Chem. 276, 32282-32287 (2001).
55. Tamaru, H and Selker, E.U. A histone H3 methyltransferase controls DNA methylation in Neurospora crassa. Nature 414, 277-283 (2001).
56. Jackson, J.P., Lindroth, A.M., Cao, X and Jacobsen, S.E. Control of CpNpG DNA methylation by the KRYPTONITE histone H3 methyltransferase. Nature 416, 556-560 (2002).
57. Wolffe, A.P and Guschin, D. Review: Chromatin structural features and targets that regulate transcription. J. Struct. Biol. 129, 102-122 (2000).
58. Grewal, S.I. and Elgin, S.C. Heterochromatin: New possibilities for the inheritance of structure. Curr. Opin. Genet. Dev. 12, 178-187 (2002).
59. Watt, F and Molloy, P. Cytosine methylation prevents binding to DNA of a HeLa cell transcription factor required for optimal expression of the adenovirus major late promoter. Genes Dev. 2, 1136-1143 (1988).
60. Bell, A.C., West, A.G and Felsenfeld, G. The protein CTCF is required for the enhancer blocking activity of vertebrate insulators. Cell 98, 387-396 (1999).
61. Ohlsson, R., Renkawitz, R and Lobanenkov, V. CTCF is a uniquely versatile transcription regulator linked to epigenetics and disease. Trends Genet. 17, 520-527 (2001).
62. Hark, A.T. et al. CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus. Nature 405, 486-489 (2000).
63. Tate, P.H and Bird, A.P. Effects of DNA methylation on DNA-binding proteins and gene expression. Curr. Opin. Genet. Dev. 3, 226-231 (1993).
64. Lewis, J.D. et al. Purification, sequence, and cellular localization of a novel chromosomal protein that binds to methylated DNA. Cell 69, 905-914 (1992).
65. Hendrich, B and Bird, A. Identification and characterization of a family of mammalian methyl-CpG binding proteins. Mol. Cell. Biol. 18, 6538-6547 (1998).
66. Prokhortchouk, A. et al. The p120 catenin partner Kaiso is a DNA methylation-dependent transcriptional repressor. Genes Dev. 15, 1613-1618 (2001).
67. Nan, X., Meehan, R.R and Bird, A. Dissection of the methyl-CpG binding domain from the chromosomal protein MeCP2. Nucleic Acids Res. 21, 4886-4892 (1993).
68. Billard, L.M., Magdinier, F., Lenoir, G.M., Frappart, L and Dante, R. MeCP2 and MBD2 expression during normal and pathological growth of the human mammary gland. Oncogene 21, 2704-2712 (2002).
69. Rietveld, L.E., Caldenhoven, E and Stunnenberg, H.G. In vivo repression of an ery-throid-specific gene by distinct corepressor complexes. EMBO J. 21, 1389-1397 (2002).
70. El-Osta, A., Kantharidis, P., Zalcberg, J.R and Wolffe, A.P. Precipitous release of methyl-CpG binding protein 2 and histone deacetylase 1 from the methylated human multidrug resistance gene (MDR1) on activation. Mol. Cell. Biol. 22, 1844-1857 (2002).
71. Boyes, J and Bird, A. DNA methylation inhibits transcription indirectly via a methyl-CpG binding protein. Cell 64, 1123-1134 (1991).
72. Jones, P.L. et al. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat. Genet. 19, 187-191 (1998).
73. Nan, X. et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393, 386-389 (1998).
74. Ng, H. et al. MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex. Nat. Genet. 23, 58-61 (1999).
75. Feng, Q and Zhang, Y. The MeCP1 complex represses transcription through preferential binding, remodeling, and deacetylating methylated nucleosomes. Genes Dev. 15, 827-832 (2001).
76. Hendrich, B., Guy, J., Ramsahoye, B., Wilson, V.A and Bird, A. Closely related proteins MBD2 and MBD3 play distinctive but interacting roles in mouse development. Genes Dev. 15, 710-723 (2001).
77. Zhang, Y. et al. Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation. Genes Dev. 13, 1924-1935 (1999).
78. Hutchins, A.S. et al. Gene silencing quantitatively controls the function of a developmental trans-activator. Mol. Cell 10, 81-91 (2002).
79. Curradi, M., Izzo, A., Badaracco, G and Landsberger, N. Molecular mechanisms of gene silencing mediated by DNA methylation. Mol. Cell. Biol. 22, 3157-3173 (2002).
80. Guy, J., Hendrich, B., Holmes, M., Martin, J.E and Bird, A. A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat. Genet. 27, 322-326 (2001).
81. Amir, R.E. et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat. Genet.23, 185-188 (1999).
82. Yusufzai, T.M and Wolffe, A.P. Functional consequences of Rett syndrome mutations on human MeCP2. Nucleic Acids Res.28, 4172-4179 (2000).
83. Free, A. et al. DNA recognition by the methyl-CpG binding domain of MeCP2. J. Biol. Chem. 276, 3353-3360 (2001).
84. Chen, R., Akbarian, S., Tudor, M and Jaenisch, R. Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. Nat. Genet.27, 327-331 (2001).
85. Shahbazian, M. et al. Mice with truncated MeCP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3. Neuron35, 243-254 (2002).
86. Tudor, M., Akbarian, S., Chen, R.Z and Jaenisch, R. Transcriptional profiling of a mouse model for Rett syndrome reveals subtle transcriptional changes in the brain. Proc. Natl. Acad. Sci. USA 99, 15536-15541 (2002).
87. Futscher, B.W. et al. Role for DNA methylation in the control of cell type specific maspin expression. Nat. Genet.31, 175-179 (2002).
88. Stancheva, I., El-Maarri, O., Walter, J., Niveleau, A and Meehan, R.R. DNA methyla-tion at promoter regions regulates the timing of gene activation in Xenopuslae-visembryos. Dev. Biol. 243, 155-165 (2002).
89. Avner, P and Heard, E. X-chromosome inactivation: Counting, choice and initiation. Nat. Rev. Genet. 2, 59-67 (2001).
90. Jones, B.K., Levorse, J.M and Tilghman, S.M. Igf2 imprinting does not require its own DNA methylation or H19RNA. Genes Dev.12, 2200-2207 (1998).
91. Cohen, D.E and Lee, J.T. X-chromosome inactivation and the search for chromosome-wide silencers. Curr. Opin. Genet. Dev. 12, 219-224 (2002).
92. Lyle, R. et al. The imprinted antisense RNA at the Igf2r locus overlaps but does not imprint Mas1. Nat. Genet.25, 19-21 (2000).
93. Chao, W., Huynh, K.D., Spencer, R.J., Davidow, L.S and Lee, J.T. CTCF, a candidate trans-acting factor for X-inactivation choice. Science 295, 345-347 (2002).
94. Brannan, C.I and Bartolomei, M.S. Mechanisms of genomic imprinting. Curr. Opin. Genet. Dev. 9, 164-170 (1999).
95. Li, E., Beard, C and Jaenisch, R. Role for DNA methylation in genomic imprinting. Nature 366, 362-385 (1993).
96. Beard, C., Li, E and Jaenisch, R. Loss of methylation activates Xist in somatic but not in embryonic cells. Genes Dev.9, 2325-2334 (1995).
97. Lee, J. et al. Erasing genomic imprinting memory in mouse clone embryos produced from day 11.5 primordial germ cells. Development 129, 1807-1817 (2002).
98. Hajkova, P. et al. Epigenetic reprogramming in mouse primordial germ cells. Mech. Dev. 117, 15 (2002).
99. Tucker, K. et al. Germ-line passage is required for establishment of methylation and expression patterns of imprinted but not of non-imprinted genes. Genes Dev. 10, 1008-1020 (1996).
100. Keohane, A.M., O’Neill, L.P., Belyaev, N.D., Lavender, J.S and Turner, B.M. X-inacti-vation and histone H4 acetylation in embryonic stem cells. Dev. Biol. 180, 618-630 (1996).
101. Wutz, A and Jaenisch, R. A shift from reversible to irreversible X inactivation is triggered during ES cell differentiation. Mol. Cell5, 695-705 (2000).
102. Csankovszki, G., Nagy, A and Jaenisch, R. Synergism of Xist RNA, DNA methylation, and histone hypoacetylation in maintaining X chromosome inactivation. J. Cell Biol. 153, 773-784 (2001).
103. Rideout, W.M., Eggan, K and Jaenisch, R. Nuclear cloning and epigenetic repro-gramming of the genome. Science 293, 1093-1098 (2001).
104. Young, L.E., Sinclair, K.D and Wilmut, I. Large offspring syndrome in cattle and sheep. Rev. Reprod.3, 155-163 (1998).
105. Ogonuki, N. et al. Early death of mice cloned from somatic cells. Nat. Genet.30, 253-254 (2002).
106. Tamashiro, K.L. et al. Cloned mice have an obese phenotype not transmitted to their offspring. Nat. Med. 8, 262-267 (2002).
107. Hochedlinger, K and Jaenisch, R. Nuclear transplantation: Lessons from frogs and mice. Curr. Opin. Cell Biol.14, 741-748 (2002).
108. Dean, W. et al. Conservation of methylation reprogramming in mammalian development: Aberrant reprogramming in cloned embryos. Proc. Natl. Acad. Sci. USA 98, 13734-13738 (2001).
109. Kang, Y. et al. Aberrant methylation of donor genome in cloned bovine embryos. Nat. Genet. 28, 173-177 (2001).
110. Bourc’his, D. et al. Delayed and incomplete reprogramming of chromosome methylation patterns in bovine cloned embryos. Curr. Biol. 11, 1542-1546 (2001).
111. Boiani, M., Eckardt, S., Scholer, H.R and McLaughlin, K.J. Oct4 distribution and level in mouse clones: Consequences for pluripotency. Genes Dev. 16, 1209-1219 (2002).
112. Bortvin, A. et al. Incomplete reactivation of Oct4-related gene in mouse embryos cloned from somatic nuclei. Development (in the press).
113. Nichols, J. et al. Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell95, 379-391 (1998).
114. Humpherys, D. et al. Epigenetic instability in ES cells and cloned mice. Science 293, 95-97 (2001).
115. Humpherys, D. et al. Abnormal gene expression in cloned mice derived from ES cell and cumulus cell nuclei. Proc. Natl. Acad. Sci. USA 99, 12889-12894 (2002).
116. Inoue, K. et al. Faithful expression of imprinted genes in cloned mice. Science 295, 297 (2002).
117. Eggan, K. et al. X-chromosome inactivation in cloned mouse embryos. Science 290, 1578-1581 (2000).
118. Wakayama, T. et al. Cloning of mice to six generations. Nature 407, 318-319 (2000).
119. Lanza, R. et al. Extension of cell life-span and telomere length in animals cloned from senescent somatic cells. Science 288, 665-669 (2000).
120. Betts, D. et al. Reprogramming of telomerase activity and rebuilding of telomere length in cloned cattle. Proc. Natl. Acad. Sci. USA 98, 1077-1082 (2001).
121. Rideout, W.M. et al. Generation of mice from wild-type and targeted ES cells by nuclear cloning. Nat. Genet. 24, 109-110 (2000).
122. Wakayama, T and Yanagimachi, R. Mouse cloning with nucleus donor cells of different age and type. Mol. Reprod. Dev. 58, 376-383 (2001).
123. Eggan, K. et al. Hybrid vigor, fetal overgrowth, and viability of mice derived by nuclear cloning and tetraploid embryo complementation. Proc. Natl. Acad. Sci. USA 98, 6209-6214 (2001).
124. Hochedlinger, K and Jaenisch, R. Monoclonal mice generated by nuclear transfer from mature B and T donor cells. Nature 415, 1035-1038 (2002).
125. Di Berardino, M.A. Genetic stability and modulation of metazoan nuclei transplanted into eggs and oocytes. Differentiation 17, 17-30 (1980).
126. Gurdon, J.B. Genetic reprogramming following nuclear transplantation in Amphibia. Semin. Cell Dev. Biol. 10, 239-243 (1999).
127. Jaenisch, R and Wilmut, I. Developmental biology. Don’t clone humans! Science 291, 2552 (2001).
128. Rideout, W.M. 3rd, Hochedlinger, K., Kyba, M., Daley, G.Q and Jaenisch, R. Correction of a genetic defect by nuclear transplantation and combined cell and gene therapy. Cell 109, 17-27 (2002).
129. Jones, P.A and Baylin, S.B. The fundamental role of epigenetic events in cancer. Nat. Rev. Genet. 3, 415-428 (2002).
130. Esteller, M and Herman, J.G. Cancer as an epigenetic disease: DNA methylation and chromatin alterations in human tumours. J. Pathol. 196, 1-7 (2002).
131. Feinberg, A.P and Vogelstein, B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 301, 89-92 (1983).
132. Gama-Sosa, M.A. et al. The 5-methylcytosine content of DNA from human tumors. Nucleic Acids Res. 11, 6883-6894 (1983).
133. Jones, P.A. DNA methylation and cancer. Oncogene 21, 5358-5360 (2002).
134. Gonzalgo, M and Jones, P. Mutagenic and epigenetic effects of DNA methylation. Mutat. Res. 386, 107-118 (1997).
135. Jones, P and Laird, P. Cancer epigenetics comes of age. Nat. Genet. 21, 163-167 (1999).
136. Xu, G.-L. et al. Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature 402, 187-191 (1999).
137. Ehrlich, M. et al. High frequencies of ICF syndrome-like pericentromeric heterochromatin decondensation and breakage in chromosome 1 in a chorionic villus sample. J. Med. Genet. 38, 882-884 (2001).
138. Chen, R.Z., Pettersson, U., Beard, C., Jackson-Grusby, L and Jaenisch, R. DNA hypomethylation leads to elevated mutation rates. Nature 395, 89-93 (1998).
139. Chan, M.F. et al. Reduced rates of gene loss, gene silencing, and gene mutation in Dnmt1-deficient embryonic stem cells. Mol. Cell. Biol. 21, 7587-7600 (2001).
140. Turker, M.S. Gene silencing in mammalian cells and the spread of DNA methylation. Oncogene 21, 5388-5393 (2002).
141. Biniszkiewicz, D. et al. Dnmt1 overexpression causes genomic hypermethylation, loss of imprinting, and embryonic lethality. Mol. Cell. Biol. 22, 2124-2135 (2002).
142. Sheldon, C.C. et al. The control of flowering by vernalization. Curr. Opin. Plant Biol. 3, 418-422 (2000).
143. Sheldon, C.C., Rouse, D.T., Finnegan, E.J., Peacock, W.J and Dennis, E.S. The molecular basis of vernalization: The central role of FLOWERING LOCUS C(FLC). Proc. Natl. Acad. Sci. USA 97, 3753-3758 (2000).
144. Sheldon, C.C. et al. The FLF MADS box gene: A repressor of flowering in Arabidopsis regulated by vernalization and methylation. Plant Cell 11, 445-458 (1999).
145. Gendall, A.R., Levy, Y.Y., Wilson, A and Dean, C. The VERNALIZATION 2 gene mediates the epigenetic regulation of vernalization in Arabidopsis. Cell 107, 525-535 (2001).
146. Brock, H.W and van Lohuizen, M. The Polycomb group—no longer an exclusive club? Curr. Opin. Genet. Dev. 11, 175-181 (2001).
147. Wilson, V.L and Jones, P.A. DNA methylation decreases in aging but not in immortal cells. Science220, 1055-1057 (1983).
148. Mays-Hoopes, L., Chao, W., Butcher, H.C and Huang, R.C. Decreased methylation of the major mouse long interspersed repeated DNA during aging and in myeloma cells. Dev. Genet. 7, 65-73 (1986).
149. Wilson, V.L., Smith, R.A., Ma, S and Cutler, R.G. Genomic 5-methyldeoxycytidine decreases with age. J. Biol. Chem. 262, 9948-9951 (1987).
150. Bestor, T.H. and Tycko, B. Creation of genomic methylation patterns. Nat. Genet. 12, 363-367 (1996).
151. Barbot, W., Dupressoir, A., Lazar, V and Heidmann, T. Epigenetic regulation of an IAP retrotransposon in the aging mouse: Progressive demethylation and de-silencing of the element by its repetitive induction. Nucleic Acids Res. 30, 2365-2373 (2002).
152. Issa, J.P. et al. Methylation of the oestrogen receptor CpG island links aging and neoplasia in human colon. Nat. Genet. 7, 536-540 (1994).
153. Toyota, M. et al. CpG island methylator phenotype in colorectal cancer. Proc. Natl. Acad. Sci. USA 96, 8681-8686 (1999).
154. Toyota, M and Issa, J.P. CpG island methylator phenotypes in aging and cancer. Semin. Cancer Biol. 9, 349-357 (1999).
155. Van Den Veyver, I.B. Genetic effects of methylation diets. Annu. Rev. Nutr. 22, 255-282 (2002).
156. Giovannucci, E. et al. Folate, methionine, and alcohol intake and risk of colorectal adenoma. J. Natl. Cancer Inst.85, 875-884 (1993).
157. Blount, B.C. et al. Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: Implications for cancer and neuronal damage. Proc. Natl. Acad. Sci. USA 94, 3290-3295 (1997).
158. Jacob, R.A. The role of micronutrients in DNA synthesis and maintenance. Adv. Exp. Med. Biol. 472, 101-113 (1999).
159. Group, M.V.S.R. Prevention of neural tube defects: Results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group. Lancet 338, 131-137 (1991).
160. Friso, S. et al. A common mutation in the 5, 10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status. Proc. Natl. Acad. Sci. USA 99, 5606-5611 (2002).
161. Dizik, M., Christman, J.K and Wainfan, E. Alterations in expression and methyla-tion of specific genes in livers of rats fed a cancer promoting methyl-deficient diet. Carcinogenesis 12, 1307-1312 (1991).
162. Poirier, L., Zapisek, W. and Lyon-Cook, B. Physiological methylation in carcinogene-sis. In Mutation and the EnvironmentPart D, 97-112 (Willey-Liss, 1990).
163. Wainfan, E and Poirier, L.A. Methyl groups in carcinogenesis: Effects on DNA methylation and gene expression. Cancer Res. 52, 2071s-2077s (1992).
164. Hoal-van Helden, E.G and van Helden, P.D. Age-related methylation changes in DNA may reflect the proliferative potential of organs. Mutat. Res. 219, 263-266 (1989).
165. Christman, J.K., Sheikhnejad, G., Dizik, M., Abileah, S and Wainfan, E. Reversibility of changes in nucleic acid methylation and gene expression induced in rat liver by severe dietary methyl deficiency. Carcinogenesis 14, 551-557 (1993).
166. Michaud, E.J. et al. Differential expression of a new dominant agouti allele (Aiapy) is correlated with methylation state and is influenced by parental lineage. Genes Dev.8, 1463-1472 (1994).
167. Millar, S.E., Miller, M.W., Stevens, M.E. and Barsh, G.S. Expression and transgenic studies of the mouse agoutigene provide insight into the mechanisms by which mammalian coat color patterns are generated. Development 121, 3223-3232 (1995).
168. Siracusa, L.D. et al. Hypervariable yellow (Ahvy), a new murine agouti mutation: Ahvy displays the largest variation in coat color phenotypes of all known agouti alleles. J. Hered.86, 121-128 (1995).
169. Wolff, G.L., Kodell, R.L., Moore, S.R and Cooney, C.A. Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice. Faseb J. 12, 949-957 (1998).
170. Cooney, C.A., Dave, A.A and Wolff, G.L. Maternal methyl supplements in mice affect epigenetic variation and DNA methylation of offspring. J. Nutr. 132, 2393S-2400S (2002).
171. Morgan, H.D., Sutherland, H.G.E., Martin, D.I.K and Whitelaw, E. Epigenetic inheritance at the agouti locus in the mouse. Nat. Genet. 23, 314-318 (1999).
172. Petronis, A. Human morbid genetics revisited: Relevance of epigenetics. Trends Genet. 17, 142-146 (2001).
173. Tremolizzo, L. et al. An epigenetic mouse model for molecular and behavioral neuropathologies related to schizophrenia vulnerability. Proc. Natl. Acad. Sci. USA 99, 17095-17100 (2002).
174. Adorjan, P. et al. Tumour class prediction and discovery by microarray-based DNA methylation analysis. Nucleic Acids Res.30, e21 (2002).
175. Jenuwein, T and Allis, C.D. Translating the histone code. Science 293, 1074-1080 (2001).
176. Santini, V., Kantarjian, H.M and Issa, J.P. Changes in DNA methylation in neoplasia: Pathophysiology and therapeutic implications. Ann. Intern. Med. 134, 573-586 (2001).
177. Juttermann, R., Li, E and Jaenisch, R. Toxicity of 5-aza-2’-deoxycytidine to mammalian cells is mediated primarily by covalent trapping of DNA methyltrans-ferase rather than DNA demethylation. Proc. Natl. Acad. Sci. USA 91, 11797-11801 (1994).
178. Cameron, E.E., Bachman, K.E., Myohanen, S., Herman, J.G and Baylin, S.B. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat. Genet 21, 103-107 (1999).
179. Jaenisch, R., Schnieke, A and Harbers, K. Treatment of mice with 5-azacytidine efficiently activates silent retroviral genomes in different tissues. Proc. Natl. Acad. Sci. USA 82, 1451-1455 (1985).
180. Millar, C.B. et al. Enhanced CpG mutability and tumorigenesis in MBD4-deficient mice. Science 297, 403-405 (2002).
181. Lagger, G. et al. Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression. EMBO J. 21, 2672-2681 (2002).
182. Peters, A.H. et al. Loss of the Suv39h histone methyltransferases impairs mammalian heterochromatin and genome stability. Cell 107, 323-337 (2001).
183. Baylin, S.B and Herman, J.G. DNA hypermethylation in tumorigenesis: Epigenetics joins genetics. Trends Genet. 16, 168-174 (2000).
184. Laird, P.W. et al. Suppression of intestinal neoplasia by DNA hypomethylation. Cell 81, 197-205 (1995).
185. Fuks, F. et al. The methyl-CpG-binding protein MeCP2 links DNA methylation to histone methylation. J. Biol. Chem. (2002); advanced online publication 9 November 2002 (doi: 10.1074/jbc.M210256200).
186. Argeson, A., Nelson, K and Siracusa, L. Molecular basis of the pleiotropic pheno-type of mice carrying the hypervariable yellow (Ahvy) mutation at the agouti locus. Genetics 142, 557-567 (1996).