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Functions of DNA methylation: islands, start sites, gene bodies and beyond

Key Points

  • DNA methylation is an epigenetic mark that can be mitotically inherited and is involved in adding stability to the repression of transcription when it is located at the start sites of mammalian genes. Our ability to obtain complete methylomes has transformed our appreciation of the role of DNA methylation in epigenetic processes.

  • DNA methylation in the bodies of genes has long been ignored but might be involved in differential promoter usage and also in transcription elongation and alternative splicing. Repetitive DNA from intragenomic parasites is heavily methylated, which allows transcription of the host gene at the same time as preventing transcription initiation of the repetitive DNA.

  • Methylation of control regions outside of the transcription start sites — such as enhancers and insulators — is increasingly being recognized as being functionally important.

  • Demethylation of DNA is now accepted as being essential for embryonic development and seems to occur mainly in regions of DNA that are not CpG islands; thus, methylation patterns are increasingly being realized as being far more dynamic than previously recognized.

Abstract

DNA methylation is frequently described as a 'silencing' epigenetic mark, and indeed this function of 5-methylcytosine was originally proposed in the 1970s. Now, thanks to improved genome-scale mapping of methylation, we can evaluate DNA methylation in different genomic contexts: transcriptional start sites with or without CpG islands, in gene bodies, at regulatory elements and at repeat sequences. The emerging picture is that the function of DNA methylation seems to vary with context, and the relationship between DNA methylation and transcription is more nuanced than we realized at first. Improving our understanding of the functions of DNA methylation is necessary for interpreting changes in this mark that are observed in diseases such as cancer.

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Figure 1: Molecular anatomy of CpG sites in chromatin and their roles in gene expression.
Figure 2: Silencing precedes DNA methylation.

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References

  1. Holliday, R. & Pugh, J. E. DNA modification mechanisms and gene activity during development. Science 187, 226–232 (1975).

    CAS  PubMed  Google Scholar 

  2. Riggs, A. D. X inactivation, differentiation, and DNA methylation. Cytogenet. Cell Genet. 14, 9–25 (1975).

    CAS  PubMed  Google Scholar 

  3. Cokus, S. J. et al. Shotgun bisulphite sequencing of the Arabidopsis genome reveals DNA methylation patterning. Nature 452, 215–219 (2008). This was the first paper to provide single-base resolution of DNA methylation genome-wide.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Rountree, M. R. & Selker, E. U. DNA methylation inhibits elongation but not initiation of transcription in Neurospora crassa. Genes Dev. 11, 2383–2395 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Lister, R. et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462, 315–322 (2009). This was the first report of a human methylome at single-base resolution.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Smallwood, S. A. et al. Dynamic CpG island methylation landscape in oocytes and preimplantation embryos. Nature Genet. 43, 811–814 (2011).

    CAS  PubMed  Google Scholar 

  7. Illingworth, R. S. & Bird, A. P. CpG islands—'a rough guide'. FEBS Lett. 583, 1713–1720 (2009).

    CAS  PubMed  Google Scholar 

  8. Takai, D. & Jones, P. A. Comprehensive analysis of CpG islands in human chromosomes 21 and 22. Proc. Natl Acad. Sci. USA 99, 3740–3745 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Moarefi, A. H. & Chedin, F. ICF syndrome mutations cause a broad spectrum of biochemical defects in DNMT3B-mediated de novo DNA methylation. J. Mol. Biol. 409, 758–772 (2011).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  11. Bhutani, N. et al. Reprogramming towards pluripotency requires AID-dependent DNA demethylation. Nature 463, 1042–1047 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Ooi, S. K. et al. DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature 448, 714–717 (2007). This paper provided a structural basis to the mechanisms of de novo methylation and showed how active histone marks could exclude methylation of DNA.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 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 

  14. 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). This was a key paper in defining the need for DNA cytosine methylation in mammals.

    Article  CAS  PubMed  Google Scholar 

  15. Jackson-Grusby, L. et al. Loss of genomic methylation causes p53-dependent apoptosis and epigenetic deregulation. Nature Genet. 27, 31–39 (2001).

    CAS  PubMed  Google Scholar 

  16. Chen, T. et al. Complete inactivation of DNMT1 leads to mitotic catastrophe in human cancer cells. Nature Genet. 39, 391–396 (2007).

    CAS  PubMed  Google Scholar 

  17. Tsumura, A. et al. Maintenance of self-renewal ability of mouse embryonic stem cells in the absence of DNA methyltransferases Dnmt1, Dnmt3a and Dnmt3b. Genes Cells 11, 805–814 (2006).

    CAS  PubMed  Google Scholar 

  18. Challen, G. A. et al. Dnmt3a is essential for hematopoietic stem cell differentiation. Nature Genet. 44, 23–31 (2011).

    PubMed  Google Scholar 

  19. Ooi, S. K. & Bestor, T. H. The colorful history of active DNA demethylation. Cell 133, 1145–1148 (2008).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Branco, M. R., Ficz, G. & Reik, W. Uncovering the role of 5-hydroxymethylcytosine in the epigenome. Nature Rev. Genet. 13, 7–13 (2012).

    CAS  Google Scholar 

  22. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Cortellino, S. et al. Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair. Cell 146, 67–79 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Cortazar, D. et al. Embryonic lethal phenotype reveals a function of TDG in maintaining epigenetic stability. Nature 470, 419–423 (2011).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    Google Scholar 

  29. Baylin, S. B. & Jones, P. A. A decade of exploring the cancer epigenome — biological and translational implications. Nature Rev. Cancer 11, 726–734 (2011).

    CAS  Google Scholar 

  30. Kelly, T. K. et al. H2A.Z maintenance during mitosis reveals nucleosome shifting on mitotically silenced genes. Mol. Cell 39, 901–911 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Gal-Yam, E. N. et al. Constitutive nucleosome depletion and ordered factor assembly at the GRP78 promoter revealed by single molecule footprinting. PLoS Genet. 2, e160 (2006).

    PubMed  PubMed Central  Google Scholar 

  32. Taberlay, P. C. et al. Polycomb-repressed genes have permissive enhancers that initiate reprogramming. Cell 147, 1283–1294 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  34. Han, H. et al. DNA methylation directly silences genes with non-CpG island promoters and establishes a nucleosome occupied promoter. Hum. Mol. Genet. 20, 4299–4310 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Weber, M. et al. Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells. Nature Genet. 37, 853–862 (2005).

    CAS  PubMed  Google Scholar 

  36. 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).

    PubMed  PubMed Central  Google Scholar 

  37. Hashimshony, T., Zhang, J., Keshet, I., Bustin, M. & Cedar, H. The role of DNA methylation in setting up chromatin structure during development. Nature Genet. 34, 187–192 (2003).

    CAS  PubMed  Google Scholar 

  38. Kass, S. U., Landsberger, N. & Wolffe, A. P. DNA methylation directs a time-dependent repression of transcription initiation. Curr. Biol. 7, 157–165 (1997).

    CAS  PubMed  Google Scholar 

  39. Venolia, L. & Gartler, S. M. Comparison of transformation efficiency of human active and inactive X-chromosomal DNA. Nature 302, 82–83 (1983). This is a key paper that unequivocally established that the covalent application of methyl groups to DNA could result in silencing and is involved in X-chromosome inactivation.

    CAS  PubMed  Google Scholar 

  40. 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). This paper unexpectedly showed that methylation of cytosine was not the primary silencing mechanism for X inactivation.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  42. Schlesinger, Y. et al. Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nature Genet. 39, 232–236 (2007).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  44. Irizarry, R. A. et al. The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nature Genet. 41, 178–186 (2009).

    CAS  PubMed  Google Scholar 

  45. You, J. S. et al. OCT4 establishes and maintains nucleosome-depleted regions that provide additional layers of epigenetic regulation of its target genes. Proc. Natl Acad. Sci. USA 108, 14497–14502 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Zilberman, D., Coleman-Derr, D., Ballinger, T. & Henikoff, S. Histone H2A.Z and DNA methylation are mutually antagonistic chromatin marks. Nature 456, 125–129 (2008). This paper showed the importance of histone variants in relation to DNA methylation. Previously, most of the focus was on histone modification.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Conerly, M. L. et al. Changes in H2A.Z occupancy and DNA methylation during B-cell lymphomagenesis. Genome Res. 20, 1383–1390 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Williams, K., Christensen, J. & Helin, K. DNA methylation: TET proteins—guardians of CpG islands? EMBO Rep. 13, 28–35 (2011).

    PubMed  PubMed Central  Google Scholar 

  50. Jones, P. A. et al. De novo methylation of the MyoD1 CpG island during the establishment of immortal cell lines. Proc. Natl Acad. Sci. USA 87, 6117–6121 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Hitchins, M. P. et al. Dominantly inherited constitutional epigenetic silencing of MLH1 in a cancer-affected family is linked to a single nucleotide variant within the 5′UTR. Cancer Cell 20, 200–213 (2011). This study demonstrated that single-nucleotide variants that decrease promoter activity can lead to preferential allele-specific methylation.

    CAS  PubMed  Google Scholar 

  52. Boumber, Y. A. et al. An Sp1/Sp3 binding polymorphism confers methylation protection. PLoS Genet. 4, e1000162 (2008).

    PubMed  PubMed Central  Google Scholar 

  53. Rideout, W. M., I. I. I., Coetzee, G. A., Olumi, A. F. & Jones, P. A. 5-Methylcytosine as an endogenous mutagen in the human LDL receptor and p53 genes. Science 249, 1288–1290 (1990).

    CAS  PubMed  Google Scholar 

  54. Jones, P. A. The DNA methylation paradox. Trends Genet. 15, 34–37 (1999).

    CAS  PubMed  Google Scholar 

  55. Illingworth, R. S. et al. Orphan CpG islands identify numerous conserved promoters in the mammalian genome. PLoS Genet. 6, e1001134 (2010).

    PubMed  PubMed Central  Google Scholar 

  56. Wolf, S. F., Jolly, D. J., Lunnen, K. D., Friedmann, T. & Migeon, B. R. Methylation of the hypoxanthine phosphoribosyltransferase locus on the human X chromosome: implications for X-chromosome inactivation. Proc. Natl Acad. Sci. USA 81, 2806–2810 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Hellman, A. & Chess, A. Gene body-specific methylation on the active X chromosome. Science 315, 1141–1143 (2007).

    CAS  PubMed  Google Scholar 

  58. Feng, S. et al. Conservation and divergence of methylation patterning in plants and animals. Proc. Natl Acad. Sci. USA 107, 8689–8694 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Larsen, F., Solheim, J. & Prydz, H. A methylated CpG island 3′ in the apolipoprotein-E gene does not repress its transcription. Hum. Mol. Genet. 2, 775–780 (1993).

    CAS  PubMed  Google Scholar 

  60. Maunakea, A. K. et al. Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature 466, 253–257 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Nguyen, C. et al. Susceptibility of nonpromoter CpG islands to de novo methylation in normal and neoplastic cells. J. Natl Cancer Inst. 93, 1465–1472 (2001).

    CAS  PubMed  Google Scholar 

  62. Nguyen, C. T., Gonzales, F. A. & Jones, P. A. Altered chromatin structure associated with methylation-induced gene silencing in cancer cells: correlation of accessibility, methylation, MeCP2 binding and acetylation. Nucleic Acids Res. 29, 4598–4606 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Yoder, J. A., Walsh, C. P. & Bestor, T. H. Cytosine methylation and the ecology of intragenomic parasites. Trends Genet. 13, 335–340 (1997). This paper pointed out the crucial role of 5mC in suppressing the transcription of transposable elements.

    CAS  PubMed  Google Scholar 

  64. Hahn, M. A., Wu, X., Li, A. X., Hahn, T. & Pfeifer, G. P. Relationship between gene body DNA methylation and intragenic H3K9me3 and H3K36me3 chromatin marks. PLoS ONE 6, e18844 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Schwartz, S., Meshorer, E. & Ast, G. Chromatin organization marks exon-intron structure. Nature Struct. Mol. Biol. 16, 990–995 (2009).

    CAS  Google Scholar 

  67. Chodavarapu, R. K. et al. Relationship between nucleosome positioning and DNA methylation. Nature 466, 388–392 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Shukla, S. et al. CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing. Nature 479, 74–79 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Lister, R. et al. Highly integrated single-base resolution maps of the epigenome in Arabidopsis. Cell 133, 523–536 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Stadler, M. B. et al. DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature 480, 490–495 (2011).

    CAS  PubMed  Google Scholar 

  71. Schmidl, C. et al. Lineage-specific DNA methylation in T cells correlates with histone methylation and enhancer activity. Genome Res. 19, 1165–1174 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Wiench, M. et al. DNA methylation status predicts cell type-specific enhancer activity. EMBO J. 30, 3028–3039 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Saluz, H. P., Jiricny, J. & Jost, J. P. Genomic sequencing reveals a positive correlation between the kinetics of strand-specific DNA demethylation of the overlapping estradiol/glucocorticoid-receptor binding sites and the rate of avian vitellogenin mRNA synthesis. Proc. Natl Acad. Sci. USA 83, 7167–7171 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Stroud, H., Feng, S., Morey Kinney, S., Pradhan, S. & Jacobsen, S. E. 5-Hydroxymethylcytosine is associated with enhancers and gene bodies in human embryonic stem cells. Genome Biol. 12, R54 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Szulwach, K. E. et al. Integrating 5-hydroxymethylcytosine into the epigenomic landscape of human embryonic stem cells. PLoS Genet. 7, e1002154 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Williams, K. et al. TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity. Nature 473, 343–348 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Ficz, G. et al. Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation. Nature 473, 398–402 (2011).

    CAS  PubMed  Google Scholar 

  78. Wu, S. C. & Zhang, Y. Active DNA demethylation: many roads lead to Rome. Nature Rev. Mol. Cell. Biol. 11, 607–620 (2010).

    CAS  Google Scholar 

  79. Bell, A. C. & Felsenfeld, G. Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene. Nature 405, 482–485 (2000). This was a key paper showing how methylation of CTCF sites could alter insulator function by directly blocking binding of CTCF.

    CAS  PubMed  Google Scholar 

  80. Takai, D., Gonzales, F. A., Tsai, Y. C., Thayer, M. J. & Jones, P. A. Large scale mapping of methylcytosines in CTCF-binding sites in the human H19 promoter and aberrant hypomethylation in human bladder cancer. Hum. Mol. Genet. 10, 2619–2626 (2001).

    CAS  PubMed  Google Scholar 

  81. Lin, J. C. et al. Role of nucleosomal occupancy in the epigenetic silencing of the MLH1 CpG island. Cancer Cell 12, 432–444 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Wade, P. A. & Wolffe, A. P. ReCoGnizing methylated DNA. Nature Struct. Biol. 8, 575–577 (2001).

    CAS  PubMed  Google Scholar 

  83. Hsieh, C. L. Dynamics of DNA methylation pattern. Curr. Opin. Genet. Dev. 10, 224–228 (2000).

    CAS  PubMed  Google Scholar 

  84. Prendergast, G. C. & Ziff, E. B. Methylation-sensitive sequence-specific DNA binding by the c-Myc basic region. Science 251, 186–189 (1991).

    CAS  PubMed  Google Scholar 

  85. Harrington, M. A., Jones, P. A., Imagawa, M. & Karin, M. Cytosine methylation does not affect binding of transcription factor Sp1. Proc. Natl Acad. Sci. USA 85, 2066–2070 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Simonsson, S. & Gurdon, J. DNA demethylation is necessary for the epigenetic reprogramming of somatic cell nuclei. Nature Cell Biol. 6, 984–990 (2004).

    CAS  PubMed  Google Scholar 

  87. Chen, P. Y., Feng, S., Joo, J. W., Jacobsen, S. E. & Pellegrini, M. A comparative analysis of DNA methylation across human embryonic stem cell lines. Genome Biol. 12, R62 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. American Association for Cancer Research Human Epigenome Task Force & European Union, Network of Excellence & Scientific Advisory Board. Moving AHEAD with an international human epigenome project. Nature 454, 711–715 (2008).

  89. Harris, R. A. et al. Comparison of sequencing-based methods to profile DNA methylation and identification of monoallelic epigenetic modifications. Nature Biotech. 28, 1097–1105 (2010). This is a good criticial review of sequencing-based methods for studying 5mC patterns.

    CAS  Google Scholar 

  90. Huang, Y. et al. The behaviour of 5-hydroxymethylcytosine in bisulfite sequencing. PLoS ONE 5, e8888 (2010).

    PubMed  PubMed Central  Google Scholar 

  91. Cooper, D. N. & Youssoufian, H. The CpG dinucleotide and human genetic disease. Hum. Genet. 78, 151–155 (1988). This paper clearly highlighted the important role of 5mC in generating disease-causing mutations.

    CAS  PubMed  Google Scholar 

  92. The Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 474, 609–615 (2011).

  93. Stirzaker, C. et al. Extensive DNA methylation spanning the Rb promoter in retinoblastoma tumors. Cancer Res. 57, 2229–2237 (1997).

    CAS  PubMed  Google Scholar 

  94. Markl, I. D. et al. Global and gene-specific epigenetic patterns in human bladder cancer genomes are relatively stable in vivo and in vitro over time. Cancer Res. 61, 5875–5884 (2001).

    CAS  PubMed  Google Scholar 

  95. Ley, T. J. et al. DNMT3A mutations in acute myeloid leukemia. N. Engl. J. Med. 363, 2424–2433 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Figueroa, M. E. et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18, 553–567 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Bell, M. V. et al. Physical mapping across the fragile X: hypermethylation and clinical expression of the fragile X syndrome. Cell 64, 861–866 (1991).

    CAS  PubMed  Google Scholar 

  98. Xu, G. L. et al. Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature 402, 187–191 (1999).

    CAS  PubMed  Google Scholar 

  99. Sharma, S., De Carvalho, D. D., Jeong, S., Jones, P. A. & Liang, G. Nucleosomes containing methylated DNA stabilize DNA methyltransferases 3A/3B and ensure faithful epigenetic inheritance. PLoS Genet. 7, e1001286 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Ong, C. T. & Corces, V. G. Enhancer function: new insights into the regulation of tissue-specific gene expression. Nature Rev. Genet. 12, 283–293 (2011).

    CAS  PubMed  Google Scholar 

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Acknowledgements

Funding for this work was provided by the US National Institutes of Health grants 5 R37 CA 082422–082413 and 5 R01 CA 083867–083812. The author thanks C. Andreu-Vieyra and J.-S. You for help with the figures.

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Correspondence to Peter A. Jones.

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Glossary

CpG islands

CpG-rich regions of DNA that are often associated with the transcription start sites of genes and that are also found in gene bodies and intergenic regions.

Bisulphite-treated DNA

Bisulphite treatment of DNA converts cytosine to uracil but leaves 5-methylcytosine intact. Thus, 5-methylcytosine patterns can be mapped by subsequent sequencing.

Insulators

DNA elements that control interactions between enhancers and promoters.

Ten-eleven translocation

(TET). Proteins of this type were recently shown to catalyse the conversion of 5-methylcytosine to 5-hydroxymethylcytosine.

Activation-induced cytidine deaminase

(AID). An enzyme that removes the amino group from cytosine or 5-methylcytosine. It is involved in class switch recombination and DNA demethylation.

Thymine DNA glycosylase

A protein that is involved in the repair of T:G mismatches that are often caused by 5-methylcytosine deamination and that participates in DNA demethylation.

Nucleosome-depleted regions

(NDRs). Regions of DNA that are not extensively wrapped up in nucleosomes. They can be seen at transcription start sites and other regulatory regions such as enhancers.

Polycomb proteins

Polycomb proteins participate in the silencing of genes by mechanisms that do not involve DNA methylation. They often silence genes that are key regulators of differentiation.

Imprinted genes

Imprinted genes show parent-of-origin expression and are controlled by epigenetic processes, including DNA methylation.

X-chromosome inactivation

One of the two X chromosomes in female mammalian somatic cells is stably silenced by epigenetic processes, including DNA methylation, to achieve dosage compensation.

Fragile X syndrome

A developmental disorder triggered by the genetic expansion of triplet repeats near the promoter of the FMR gene, which leads to its silencing, DNA methylation and to the disease phenotype.

Immunodeficiency, centromere instability and facial anomalies syndrome

(ICF syndrome). This can be caused by mutations in DNA methyltransferase 3B (DNMT3B) and leads to centromeric instability, developmental abnormalities and immune deficiencies.

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Jones, P. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet 13, 484–492 (2012). https://doi.org/10.1038/nrg3230

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