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DNA methylation dynamics in health and disease

A Corrigendum to this article was published on 04 October 2013

This article has been updated

Abstract

DNA methylation is an epigenetic mark that is erased in the early embryo and then re-established at the time of implantation. In this Review, dynamics of DNA methylation during normal development in vivo are discussed, starting from fertilization through embryogenesis and postnatal growth, as well as abnormal methylation changes that occur in cancer.

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Figure 1: Protection of CpG islands from de novo methylation.
Figure 2: Targeted de novo methylation.
Figure 3: Pathways of demethylation.
Figure 4: Targeted demethylation.
Figure 5: DNA methylation pattern in cancer.

Change history

  • 05 June 2013

    In the version of this article initially published, on p. 274, the sentence: "One key factor appears to be ZFP57 (also known as KAP1)..." should have read: "One key factor appears to be the ZFP57-KAP1 complex...." KAP1 is a ZFP57-binding partner. The error has been corrected in the HTML and PDF versions of the article.

References

  1. Monk, M., Boubelik, M. & Lehnert, S. Temporal and regional changes in DNA methylation in the embryonic, extraembryonic and germ cell lineages during mouse embryo development. Development 99, 371–382 (1987).

    CAS  PubMed  Google Scholar 

  2. Kafri, T. et al. Developmental pattern of gene-specific DNA methylation in the mouse embryo and germline. Genes Dev. 6, 705–714 (1992).

    Article  CAS  PubMed  Google Scholar 

  3. Smith, Z.D. et al. A unique regulatory phase of DNA methylation in the early mammalian embryo. Nature 484, 339–344 (2012).This is a characterization of the dynamic changes in DNA methylation during gametogenesis and early embryogenesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Mayer, W., Niveleau, A., Walter, J., Fundele, R. & Haaf, T. Demethylation of the zygotic paternal genome. Nature 403, 501–502 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Oswald, J. et al. Active demethylation of the paternal genome in the mouse zygote. Curr. Biol. 10, 475–478 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Inoue, A. & Zhang, Y. Replication-dependent loss of 5-hydroxymethylcytosine in mouse preimplantation embryos. Science 334, 194 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Cedar, H. & Bergman, Y. Linking DNA methylation and histone modification: patterns and paradigms. Nat. Rev. Genet. 10, 295–304 (2009).

    Article  CAS  PubMed  Google Scholar 

  8. Sanford, J.P., Clark, H.J., Chapman, V.M. & Rossant, J. Differences in DNA methylation during oogenesis and spermatogenesis and their persistence during early embryogenesis in the mouse. Genes Dev. 1, 1039–1046 (1987).

    Article  CAS  PubMed  Google Scholar 

  9. Bourc'his, D., Xu, G.L., Lin, C.S., Bollman, B. & Bestor, T.H. Dnmt3L and the establishment of maternal genomic imprints. Science 294, 2536–2539 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Brandeis, M. et al. The ontogeny of allele-specific methylation associated with imprinted genes in the mouse. EMBO J. 12, 3669–3677 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Li, X. et al. A maternal-zygotic effect gene, Zfp57, maintains both maternal and paternal imprints. Dev. Cell 15, 547–557 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Mackay, D.J. et al. Hypomethylation of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57. Nat. Genet. 40, 949–951 (2008).

    Article  CAS  PubMed  Google Scholar 

  13. Wossidlo, M. et al. 5-Hydroxymethylcytosine in the mammalian zygote is linked with epigenetic reprogramming. Nat. Commun. 2, 241 (2011).

    Article  CAS  PubMed  Google Scholar 

  14. Nakamura, T. et al. PGC7/Stella protects against DNA demethylation in early embryogenesis. Nat. Cell Biol. 9, 64–71 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Nakamura, T. et al. PGC7 binds histone H3K9me2 to protect against conversion of 5mC to 5hmC in early embryos. Nature 486, 415–419 (2012).

    Article  CAS  PubMed  Google Scholar 

  16. Farthing, C.R. et al. Global mapping of DNA methylation in mouse promoters reveals epigenetic reprogramming of pluripotency genes. PLoS Genet. 4, e1000116 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Ng, R.K. et al. Epigenetic restriction of embryonic cell lineage fate by methylation of Elf5. Nat. Cell Biol. 10, 1280–1290 (2008). This report suggests that demethylation of Elf5 in the early embryo licenses extraembryonic differentiation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Koh, K.P. et al. Tet1 and Tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells. Cell Stem Cell 8, 200–213 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Maegawa, S. et al. Widespread and tissue specific age-related DNA methylation changes in mice. Genome Res. 20, 332–340 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kaminen-Ahola, N. et al. Maternal ethanol consumption alters the epigenotype and the phenotype of offspring in a mouse model. PLoS Genet. 6, e1000811 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Daxinger, L. & Whitelaw, E. Transgenerational epigenetic inheritance: more questions than answers. Genome Res. 20, 1623–1628 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Okano, M., Bell, D.W., Haber, D.A. & Li, E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99, 247–257 (1999).

    Article  CAS  PubMed  Google Scholar 

  23. Brandeis, M. et al. Sp1 elements protect a CpG island from de novo methylation. Nature 371, 435–438 (1994).

    Article  CAS  PubMed  Google Scholar 

  24. Straussman, R. et al. Developmental programming of CpG island methylation profiles in the human genome. Nat. Struct. Mol. Biol. 16, 564–571 (2009). This work shows that protection of CpG islands from de novo methylation is determined by sequence information.

    Article  CAS  PubMed  Google Scholar 

  25. Laurent, L. et al. Dynamic changes in the human methylome during differentiation. Genome Res. 20, 320–331 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. De Carvalho, D.D. et al. DNA methylation screening identifies driver epigenetic events of cancer cell survival. Cancer Cell 21, 655–667 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Cedar, H. & Bergman, Y. Programming of DNA methylation patterns. Annu. Rev. Biochem. 81, 97–117 (2012).

    Article  CAS  PubMed  Google Scholar 

  28. Lienert, F. et al. Identification of genetic elements that autonomously determine DNA methylation states. Nat. Genet. 43, 1091–1097 (2011).

    Article  CAS  PubMed  Google Scholar 

  29. Macleod, D., Charlton, J., Mullins, J. & 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).

    Article  CAS  PubMed  Google Scholar 

  30. Siegfried, Z. et al. DNA methylation represses transcription in vivo. Nat. Genet. 22, 203–206 (1999).

    Article  CAS  PubMed  Google Scholar 

  31. Goren, A. et al. Fine tuning of globin gene expression by DNA methylation. PLoS ONE 1, e46 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Weber, M. et al. Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nat. Genet. 39, 457–466 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. Meissner, A. et al. Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454, 766–770 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ooi, S.K. et al. DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature 448, 714–717 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Otani, J. et al. Structural basis for recognition of H3K4 methylation status by the DNA methyltransferase 3A ATRX-DNMT3-DNMT3L domain. EMBO Rep. 10, 1235–1241 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Clouaire, T. et al. Cfp1 integrates both CpG content and gene activity for accurate H3K4me3 deposition in embryonic stem cells. Genes Dev. 26, 1714–1728 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Pollack, Y., Stein, R., Razin, A. & Cedar, H. Methylation of foreign DNA sequences in eukaryotic cells. Proc. Natl. Acad. Sci. USA 77, 6463–6467 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yisraeli, J. et al. Muscle-specific activation of a methylated chimeric actin gene. Cell 46, 409–416 (1986).

    Article  CAS  PubMed  Google Scholar 

  39. Li, E., Bestor, T.H. & Jaenisch, R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69, 915–926 (1992).

    Article  CAS  PubMed  Google Scholar 

  40. Leonhardt, H., Page, A.W., Weier, H.U. & Bestor, T.H. A targeting sequence directs DNA methyltransferase to sites of DNA replication in mammalian nuclei. Cell 71, 865–873 (1992).

    Article  CAS  PubMed  Google Scholar 

  41. Gruenbaum, Y., Cedar, H. & Razin, A. Substrate and sequence specificity of a eukaryotic DNA methylase. Nature 295, 620–622 (1982).

    Article  CAS  PubMed  Google Scholar 

  42. Bostick, M. et al. UHRF1 plays a role in maintaining DNA methylation in mammalian cells. Science 317, 1760–1764 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Sharif, J. et al. The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA. Nature 450, 908–912 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. Sharif, J. & Koseki, H. Recruitment of Dnmt1 roles of the SRA protein Np95 (Uhrf1) and other factors. Prog. Mol. Biol. Transl. Sci. 101, 289–310 (2011).

    Article  CAS  PubMed  Google Scholar 

  45. Achour, M. et al. The interaction of the SRA domain of ICBP90 with a novel domain of DNMT1 is involved in the regulation of VEGF gene expression. Oncogene 27, 2187–2197 (2008).

    Article  CAS  PubMed  Google Scholar 

  46. David, L. et al. A high-resolution map of transcription in the yeast genome. Proc. Natl. Acad. Sci. USA 103, 5320–5325 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Petruk, S. et al. TrxG and PcG proteins but not methylated histones remain associated with DNA through replication. Cell 150, 922–933 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ben-Shushan, E., Pikarsky, E., Klar, A. & Bergman, Y. Extinction of Oct-3/4 gene expression in embryonal carcinoma x fibroblast somatic cell hybrids is accompanied by changes in the methylation status, chromatin structure, and transcriptional activity of the Oct-3/4 upstream region. Mol. Cell. Biol. 13, 891–901 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Gidekel, S. & Bergman, Y. A unique developmental pattern of Oct-3/4 DNA methylation is controlled by a cis-demodification element. J. Biol. Chem. 277, 34521–34530 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Feldman, N. et al. G9a-mediated irreversible epigenetic inactivation of Oct-3/4 during early embryogenesis. Nat. Cell Biol. 8, 188–194 (2006). This work demonstrates that de novo methylation is a late event in the inactivation of pluripotency genes but provides stability over time.

    Article  CAS  PubMed  Google Scholar 

  51. Epsztejn-Litman, S. et al. De novo DNA methylation promoted by G9a prevents reprogramming of embryonically silenced genes. Nat. Struct. Mol. Biol. 15, 1176–1183 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Keohane, A.M., Lavender, J.S., O'Neill, L.P. & Turner, B.M. Histone acetylation and X inactivation. Dev. Genet. 22, 65–73 (1998).

    Article  CAS  PubMed  Google Scholar 

  53. Plath, K. et al. Role of histone H3 lysine 27 methylation in X inactivation. Science 300, 131–135 (2003).

    Article  CAS  PubMed  Google Scholar 

  54. Silva, J. et al. Establishment of histone H3 methylation on the inactive X chromosome requires transient recruitment of Eed-Enx1 polycomb group complexes. Dev. Cell 4, 481–495 (2003).

    Article  CAS  PubMed  Google Scholar 

  55. Lock, L.F., Takagi, N. & Martin, G.R. Methylation of the HPRT gene on the inactive X occurs after chromosome inactivation. Cell 48, 39–46 (1987).

    Article  CAS  PubMed  Google Scholar 

  56. Gendrel, A.V. et al. Smchd1-dependent and -independent pathways determine developmental dynamics of CpG island methylation on the inactive x chromosome. Dev. Cell 23, 265–279 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kaslow, D.C. & Migeon, B.R. DNA methylation stabilizes X chromosome inactivation in eutherians but not in marsupials: evidence for multistep maintenance of mammalian X dosage compensation. Proc. Natl. Acad. Sci. USA 84, 6210–6214 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Wareham, K.A., Lyon, M.F., Glenister, P.H. & Williams, E.D. Age related reactivation of an X-linked gene. Nature 327, 725–727 (1987).

    Article  CAS  PubMed  Google Scholar 

  59. Lande-Diner, L. et al. Role of DNA methylation in stable gene repression. J. Biol. Chem. 282, 12194–12200 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. Liang, G. et al. Cooperativity between DNA methyltransferases in the maintenance methylation of repetitive elements. Mol. Cell. Biol. 22, 480–491 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Jones, P.A. & Liang, G. Rethinking how DNA methylation patterns are maintained. Nat. Rev. Genet. 10, 805–811 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Illingworth, R. et al. A novel CpG island set identifies tissue-specific methylation at developmental gene loci. PLoS Biol. 6, e22 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Vire, E. et al. The Polycomb group protein EZH2 directly controls DNA methylation. Nature 439, 871–874 (2006).

    Article  CAS  PubMed  Google Scholar 

  64. O'Hagan, H.M. et al. Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and polycomb members to promoter CpG Islands. Cancer Cell 20, 606–619 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Thillainadesan, G. et al. TGF-beta-dependent active demethylation and expression of the p15ink4b tumor suppressor are impaired by the ZNF217/CoREST complex. Mol. Cell 46, 636–649 (2012).

    Article  CAS  PubMed  Google Scholar 

  66. Yisraeli, J. & Szyf, M. Gene methylation patterns and expression. in DNA methylation: Biochemistry and Biological Significance (eds. Razin, A., Cedar, H. & Riggs, A.D.) 352–370 (Springer-Verlag, New York, 1984).

  67. Paroush, Z., Keshet, I., Yisraeli, J. & Cedar, H. Dynamics of demethylation and activation of the α actin gene in myoblasts. Cell 63, 1229–1237 (1990).

    Article  CAS  PubMed  Google Scholar 

  68. Lichtenstein, M., Keini, G., Cedar, H. & Bergman, Y. B-cell specific demethylation: a novel role for the intronic κ-chain enhancer sequence. Cell 76, 913–923 (1994).

    Article  CAS  PubMed  Google Scholar 

  69. Zhang, L.P., Stroud, J., Eddy, C.A., Walter, C.A. & McCarrey, J.R. Multiple elements influence transcriptional regulation from the human testis-specific PGK2 promoter in transgenic mice. Biol. Reprod. 60, 1329–1337 (1999).

    Article  CAS  PubMed  Google Scholar 

  70. Kirillov, A. et al. A role for nuclear NF-κB in B-cell-specific demethylation of the Igκ locus. Nat. Genet. 13, 435–441 (1996).

    Article  CAS  PubMed  Google Scholar 

  71. Goldmit, M. et al. Epigenetic ontogeny of the kappa locus during B cell development. Nat. Immunol. 6, 198–203 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. Stadler, M.B. et al. DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature 480, 490–495 (2011). The work shows that partially methylated regions are regulated by trans -acting factors, many of which may be enhancers.

    Article  CAS  PubMed  Google Scholar 

  73. ENCODE Project Consortium. et al. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012).

  74. Sullivan, C.H. & Grainger, R.M. δ-Crystallin genes become hypomethylated in postmitotic lens cells during chicken development. Proc. Natl. Acad. Sci. USA 84, 329–333 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Bhattacharya, S.K., Ramchandani, S., Cervoni, N. & Szyf, M. A mammalian protein with specific demethylase activity for mCpG DNA. Nature 397, 579–583 (1999).

    Article  CAS  PubMed  Google Scholar 

  76. Ng, H.H. et al. MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex. Nat. Genet. 23, 58–61 (1999).

    Article  CAS  PubMed  Google Scholar 

  77. Jost, J.P. Nuclear extracts of chicken embryos promote an active demethylation of DNA by excision repair of 5-methyldeoxycytidine. Proc. Natl. Acad. Sci. USA 90, 4684–4688 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Weiss, A., Keshet, I., Razin, A. & Cedar, H. DNA demethylation in vitro: involvement of RNA. Cell 86, 709–718 (1996).

    Article  CAS  PubMed  Google Scholar 

  79. Razin, A. et al. Replacement or 5-methylcytosine by cytosine: a possible mechanism for transient DNA demethylation during differentiation. Proc. Natl. Acad. Sci. USA 83, 2827–2831 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Wu, H. et al. Dual functions of Tet1 in transcriptional regulation in mouse embryonic stem cells. Nature 473, 389–393 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Iqbal, K., Jin, S.G., Pfeifer, G.P. & Szabo, P.E. Reprogramming of the paternal genome upon fertilization involves genome-wide oxidation of 5-methylcytosine. Proc. Natl. Acad. Sci. USA 108, 3642–3647 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Gu, T.P. et al. The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes. Nature 477, 606–610 (2011).

    Article  CAS  PubMed  Google Scholar 

  83. Wu, H. & Zhang, Y. Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. Genes Dev. 25, 2436–2452 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. He, Y.F. et al. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 333, 1303–1307 (2011). This work shows that 5mC can be oxidized by Tet to form products that are then repaired by glycosylases, thereby bringing about demethylation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  86. Hashimoto, H. et al. Recognition and potential mechanisms for replication and erasure of cytosine hydroxymethylation. Nucleic Acids Res. 40, 4841–4849 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Popp, C. et al. Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency. Nature 463, 1101–1105 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Guo, J.U., Su, Y., Zhong, C., Ming, G.L. & Song, H. Hydroxylation of 5-Methylcytosine by TET1 Promotes Active DNA Demethylation in the Adult Brain. Cell 145, 423–434 (2011). This work shows that TET1 mediates specific demethylation in the brain.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Fritz, E.L. & Papavasiliou, F.N. Cytidine deaminases: AIDing DNA demethylation? Genes Dev. 24, 2107–2114 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Rusmintratip, V. & Sowers, L.C. An unexpectedly high excision capacity for mispaired 5-hydroxymethyluracil in human cell extracts. Proc. Natl. Acad. Sci. USA 97, 14183–14187 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Nabel, C.S. et al. AID/APOBEC deaminases disfavor modified cytosines implicated in DNA demethylation. Nat. Chem. Biol. 8, 751–758 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Cedar, H. & Bergman, Y. Developmental regulation of immune system gene rearrangement. Curr. Opin. Immunol. 11, 64–69 (1999).

    Article  CAS  PubMed  Google Scholar 

  93. Engler, P. & Storb, U. Hypomethylation is necessary but not sufficient for V(D)J recombination within a transgenic substrate. Mol. Immunol. 36, 1169–1173 (1999).

    Article  CAS  PubMed  Google Scholar 

  94. Wilks, A., Seldran, M. & Jost, J.P. An estrogen-dependent demethylation of the 5′ end of the chicken vitellogenin gene is independent of DNA synthesis. Nucleic Acids Res. 12, 1163–1177 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Benvenisty, N., Mencher, D., Meyuchas, O., Razin, A. & Reshef, L. Sequential changes in DNA methylation patterns of the rat phosphoenolpyruvate carboxykinase gene during development. Proc. Natl. Acad. Sci. USA 82, 267–271 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Shemer, R. et al. Methylation changes in the apo AI gene during embryonic development of the mouse. Proc. Natl. Acad. Sci. USA 88, 10300–10304 (1991).

    Article  Google Scholar 

  97. Kunnath, L. & Locker, J. Developmental changes in the methylation of the rat albumin and alpha-fetoprotein genes. EMBO J. 2, 317–324 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Busslinger, M., Hurst, J. & Flavell, R.A. DNA methylation and the regulation of the globin gene expression. Cell 34, 197–206 (1983).

    Article  CAS  PubMed  Google Scholar 

  99. Siegfried, Z. & Cedar, H. DNA methylation: a molecular lock. Curr. Biol. 7, R305–R307 (1997).

    Article  CAS  PubMed  Google Scholar 

  100. Qian, W. et al. A histone acetyltransferase regulates active DNA demethylation in Arabidopsis. Science 336, 1445–1448 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Jones, P.A. & Baylin, S.B. The fundamental role of epigenetic events in cancer. Nat. Rev. Genet. 3, 415–428 (2002).

    Article  CAS  PubMed  Google Scholar 

  102. Jones, P.A. & Baylin, S.B. The epigenomics of cancer. Cell 128, 683–692 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Baylin, S. & Bestor, T.H. Altered methylation patterns in cancer cell genomes: cause or consequence? Cancer Cell 1, 299–305 (2002).

    Article  CAS  PubMed  Google Scholar 

  104. Gal-Yam, E.N. et al. Frequent switching of Polycomb repressive marks and DNA hypermethylation in the PC3 prostate cancer cell line. Proc. Natl. Acad. Sci. USA 105, 12979–12984 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Keshet, I. et al. Evidence for an instructive mechanism of de novo methylation in cancer cells. Nat. Genet. 38, 149–153 (2006). This work shows that de novo methylation of CpG islands in cancer occurs at fixed sites in the genome.

    Article  CAS  PubMed  Google Scholar 

  106. Zardo, G. et al. Integrated genomic and epigenomic analyses pinpoint biallelic gene inactivation in tumors. Nat. Genet. 32, 453–458 (2002).

    Article  CAS  PubMed  Google Scholar 

  107. Ohm, J.E. et al. A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat. Genet. 39, 237–242 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Schlesinger, Y. et al. Polycomb mediated histone H3(K27) methylation pre-marks genes for de novo methylation in cancer. Nat. Genet. 39, 232–236 (2007).

    Article  CAS  PubMed  Google Scholar 

  109. Widschwendter, M. et al. Epigenetic stem cell signature in cancer. Nat. Genet. 39, 157–158 (2007).

    Article  CAS  PubMed  Google Scholar 

  110. Rakyan, V.K. et al. Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domains. Genome Res. 20, 434–439 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Teschendorff, A.E. et al. Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer. Genome Res. 20, 440–446 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. An, B. et al. Characteristic methylation profile in CpG island methylator phenotype-negative distal colorectal cancers. Int. J. Cancer 127, 2095–2105 (2010).

    Article  CAS  PubMed  Google Scholar 

  113. Belshaw, N.J. et al. Patterns of DNA methylation in individual colonic crypts reveal aging and cancer-related field defects in the morphologically normal mucosa. Carcinogenesis 31, 1158–1163 (2010).

    Article  CAS  PubMed  Google Scholar 

  114. Sasaki, M. et al. IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature 488, 656–659 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. You, J.S. & Jones, P.A. Cancer genetics and epigenetics: two sides of the same coin? Cancer Cell 22, 9–20 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Feinberg, A.P. & Vogelstein, B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 301, 89–92 (1983).

    Article  CAS  PubMed  Google Scholar 

  117. Berman, B.P. et al. Regions of focal DNA hypermethylation and long-range hypomethylation in colorectal cancer coincide with nuclear lamina-associated domains. Nat. Genet. 44, 40–46 (2012). This work demonstrates that demethylation in cancer occurs at lamin-associated domains.

    Article  CAS  Google Scholar 

  118. Hon, G.C. et al. Global DNA hypomethylation coupled to repressive chromatin domain formation and gene silencing in breast cancer. Genome Res. 22, 246–258 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Laird, P.W. et al. Suppression of intestinal neoplasia by DNA hypomethylation. Cell 81, 197–205 (1995). This work shows that treatment with inhibitors of DNA methylation from birth 'prevents' the formation of intestinal tumors in genetically predisposed mice.

    Article  CAS  PubMed  Google Scholar 

  120. McCabe, M.T. et al. Inhibition of DNA methyltransferase activity prevents tumorigenesis in a mouse model of prostate cancer. Cancer Res. 66, 385–392 (2006).

    Article  CAS  PubMed  Google Scholar 

  121. Bender, C.M., Pao, M.M. & Jones, P.A. Inhibition of DNA methylation by 5-aza-2'-deoxycytidine suppresses the growth of human tumor cell lines. Cancer Res. 58, 95–101 (1998).

    CAS  PubMed  Google Scholar 

  122. Tsai, H.C. et al. Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells. Cancer Cell 21, 430–446 (2012). This report shows that demethylation agents inhibit tumors at low doses.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Belinsky, S.A. et al. Inhibition of DNA methylation and histone deacetylation prevents murine lung cancer. Cancer Res. 63, 7089–7093 (2003).

    CAS  PubMed  Google Scholar 

  124. Chen, M. et al. DNA methyltransferase inhibitor, zebularine, delays tumor growth and induces apoptosis in a genetically engineered mouse model of breast cancer. Mol. Cancer Ther. 11, 370–382 (2012).

    Article  PubMed  CAS  Google Scholar 

  125. Gaudet, F. et al. Induction of tumors in mice by genomic hypomethylation. Science 300, 489–492 (2003).

    Article  CAS  PubMed  Google Scholar 

  126. Yamada, Y. et al. Opposing effects of DNA hypomethylation on intestinal and liver carcinogenesis. Proc. Natl. Acad. Sci. USA 102, 13580–13585 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Thomson, J.P. et al. CpG islands influence chromatin structure via the CpG-binding protein Cfp1. Nature 464, 1082–1086 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by research grants from the Israel Academy of Sciences (H.C. and Y.B.), the Israel Cancer Research Foundation (H.C. and Y.B.), German Cancer Research Center (DKFZ) (Y.B.), the BSF (Y.B.), The Sur Zelman Cowen Universities Fund (Y.B.), Lew Sanders (H.C.) and Norton Herrick (H.C.).

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Correspondence to Yehudit Bergman or Howard Cedar.

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Bergman, Y., Cedar, H. DNA methylation dynamics in health and disease. Nat Struct Mol Biol 20, 274–281 (2013). https://doi.org/10.1038/nsmb.2518

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