Advertisement

Epigenomics pp 69-83 | Cite as

The Expanding View of Cytosine Methylation

  • J.M. Greally

Abstract

We are currently in an era of increased interest in the role of the epigenome in normal cellular physiology and its role in human disease. Part of this increased interest is driven by new technologies that have allowed us to gain insights never previously possible. Our view of cytosine methylation is expanding not only in terms of how much of the genome we can study at a time, but also in terms of what we think cytosine methylation might be doing functionally. While DNA methylation in mammalian cells has been studied for more than 45 years at this point (srinivasan1962), new insights are revealing the sobering reality that we understand much less about its functional consequences than we may have believed. In this review, the insights gained from new technologies to study cytosine methylation are examined so that we can redefine the paths for further exploration of this intriguing molecular regulator.

Keywords

Cytosine methylation Epigenetic CpG island CG di 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Allen, M.D., et al., Solution structure of the nonmethyl-CpG-binding CXXC domain of the leukaemia-associated MLL histone methyltransferase. EMBO J, 2006. 25(19): 4503–12.PubMedCrossRefGoogle Scholar
  2. Barton, S.C., et al., Genome-wide methylation patterns in normal and uniparental early mouse embryos. Hum Mol Genet, 2001. 10(26): 2983–7.PubMedCrossRefGoogle Scholar
  3. Bernstein, B.E., et al., A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell, 2006. 125: 315–26.PubMedCrossRefGoogle Scholar
  4. Bernstein, B.E., et al., Genomic maps and comparative analysis of histone modifications in human and mouse. Cell, 2005. 120(2): 169–81.PubMedCrossRefGoogle Scholar
  5. Bestor, T.H., The DNA methyltransferases of mammals. Hum Mol Genet, 2000. 9(16): 2395–402.PubMedCrossRefGoogle Scholar
  6. Bhasin, M., et al., Prediction of methylated CpGs in DNA sequences using a support vector machine. FEBS Lett, 2005. 579(20): 4302–8.PubMedCrossRefGoogle Scholar
  7. Bird, A.P., CpG-rich islands and the function of DNA methylation. Nature, 1986. 321(6067):209–13.PubMedCrossRefGoogle Scholar
  8. Bird, A.P., et al., Non-methylated CpG-rich islands at the human alpha-globin locus: implications for evolution of the alpha-globin pseudogene. EMBO J, 1987. 6(4): 999–1004.PubMedGoogle Scholar
  9. Bock, C., et al., CpG island methylation in human lymphocytes is highly correlated with DNA sequence, repeats, and predicted DNA structure. PLoS Genet, 2006. 2(3): e26.PubMedCrossRefGoogle Scholar
  10. Cao, R. and Y. Zhang, The functions of E(Z)/EZH2-mediated methylation of lysine 27 in histone H3. Curr Opin Genet Dev, 2004 14(2): 155–64.PubMedCrossRefGoogle Scholar
  11. Cheng, X. and R.M. Blumenthal, Mammalian DNA methyltransferases: a structural perspective. Structure, 2008. 16(3): 341–50.PubMedCrossRefGoogle Scholar
  12. Clark, S.J., J. Harrison, and M. Frommer, CpNpG methylation in mammalian cells. Nature Genet, 1995. 10(1): 20–7.PubMedCrossRefGoogle Scholar
  13. Cokus, S.J., et al., Shotgun bisulphite sequencing of the Arabidopsis genome reveals DNA methylation patterning. Nature, 2008. 452(7184): 215–9.PubMedCrossRefGoogle Scholar
  14. Down, T.A., et al., A Bayesian deconvolution strategy for immunoprecipitation-based DNA methylome analysis. Nature Biotechnol, 2008. 26(7): 779–85.CrossRefGoogle Scholar
  15. Dupont, J.M., et al., De novo quantitative bisulfite sequencing using the pyrosequencing technology. Anal Biochem, 2004. 333(1): 119–27.PubMedCrossRefGoogle Scholar
  16. Eckhardt, F., et al., DNA methylation profiling of human chromosomes 6, 20 and 22. Nature Genet, 2006.Google Scholar
  17. Ehrich, M., et al., Quantitative high-throughput analysis of DNA methylation patterns by base-specific cleavage and mass spectrometry. Proc Natl Acad Sci USA, 2005. 102(44): 15785–90.PubMedCrossRefGoogle Scholar
  18. Esteller, M., Epigenetics provides a new generation of oncogenes and tumour-suppressor genes. Br J Cancer, 2007. 96 Suppl: R26–30.PubMedGoogle Scholar
  19. Esteve, P.O., et al., Direct interaction between DNMT1 and G9a coordinates DNA and histone methylation during replication. Genes Dev, 2006. 20(22): 3089–103.PubMedCrossRefGoogle Scholar
  20. Fazzari, M.J. and J.M. Greally, Epigenomics: beyond CpG islands. Nature Rev Genet, 2004. 5(6): 446–55.CrossRefPubMedGoogle Scholar
  21. Feinberg, A.P. and B. Tycko, The history of cancer epigenetics. Nature Rev Cancer, 2004. 4(2): 143–53.CrossRefGoogle Scholar
  22. Feltus, F.A., et al., Predicting aberrant CpG island methylation. Proc Natl Acad Sci USA, 2003. 100(21): 12253–8.PubMedCrossRefGoogle Scholar
  23. Filion, G.J., et al., A family of human zinc finger proteins that bind methylated DNA and repress transcription. Mol Cell Biol, 2006. 26(1): 169–81.PubMedCrossRefGoogle Scholar
  24. Flanagan, J.M., et al., Intra- and interindividual epigenetic variation in human germ cells. Am J Hum Genet, 2006. 79(1): 67–84.PubMedCrossRefGoogle Scholar
  25. Fraga, M.F., et al., Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA, 2005. 102(30): 10604–9.PubMedCrossRefGoogle Scholar
  26. Gardiner-Garden, M. and M. Frommer, CpG islands in vertebrate genomes. J Mol Biol, 1987. 196(2): 261–82.PubMedCrossRefGoogle Scholar
  27. Gebhard, C., et al., Genome-wide profiling of CpG methylation identifies novel targets of aberrant hypermethylation in myeloid leukemia. Cancer Res, 2006. 66(12): 6118–28.PubMedCrossRefGoogle Scholar
  28. Glass, J.L., et al., CG dinucleotide clustering is a species-specific property of the genome. Nucleic Acids Res, 2007. 35(20): 6798–807.PubMedCrossRefGoogle Scholar
  29. Gottlicher, M., et al., Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J, 2001. 20(24): 6969–78.PubMedCrossRefGoogle Scholar
  30. Hatada, I., et al., Genome-wide profiling of promoter methylation in human. Oncogene, 2006. 25(21): 3059–64.PubMedCrossRefGoogle Scholar
  31. Hatchwell, E. and J.M. Greally, The potential role of epigenomic dysregulation in complex human disease. Trends Genet, 2007. 23(11): 588–95.PubMedCrossRefGoogle Scholar
  32. Hayashi, H., et al., High-resolution mapping of DNA methylation in human genome using oligonucleotide tiling array. Hum Genet, 2007. 120(5): 701–11.PubMedCrossRefGoogle Scholar
  33. Heintzman, N.D., et al., Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nature Genet, 2007. 39(3): 311–318.PubMedCrossRefGoogle Scholar
  34. Hellebrekers, D.M., A.W. Griffioen, and M. van Engeland, Dual targeting of epigenetic therapy in cancer. Biochim Biophys Acta, 2007. 1775(1): 76–91.PubMedGoogle Scholar
  35. Hendrich, B. and S. Tweedie, The methyl-CpG binding domain and the evolving role of DNA methylation in animals. Trends Genet, 2003 19(5): 269–77.PubMedCrossRefGoogle Scholar
  36. Herman, J.G., et al., Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci U S A, 1996. 93(18): 9821–6.PubMedCrossRefGoogle Scholar
  37. Hoque, M.O., et al., Genome-wide promoter analysis uncovers portions of the cancer methylome. Cancer Res, 2008. 68(8): 2661–70.PubMedCrossRefGoogle Scholar
  38. Issa, J.P., CpG island methylator phenotype in cancer. Nature Rev Cancer, 2004. 4(12): 988–93.CrossRefGoogle Scholar
  39. Jia, D., et al., Structure of Dnmt3a bound to Dnmt3L suggests a model for de novo DNA methylation. Nature, 2007. 449(7159): 248–51.PubMedCrossRefGoogle Scholar
  40. Jones P.A., et al. Moving AHEAD with an International Human Epigenome Project. Nature 2008. 454(7205): 711–715.CrossRefGoogle Scholar
  41. Kangaspeska, S., et al., Transient cyclical methylation of promoter DNA. Nature, 2008. 452(7183): 112–5.PubMedCrossRefGoogle Scholar
  42. Kerkel, K., et al., Genomic surveys by methylation-sensitive SNP analysis identify sequence-dependent allele-specific DNA methylation. Nature Genet, 2008. 40(7): 904–8.PubMedCrossRefGoogle Scholar
  43. Khulan, B., et al., Comparative isoschizomer profiling of cytosine methylation: the HELP assay. Genome Res, 2006. 16(8): 1046–55.PubMedCrossRefGoogle Scholar
  44. Kim, T.H., et al., Analysis of the vertebrate insulator protein CTCF-binding sites in the human genome. Cell, 2007. 128(6): 1231–45.PubMedCrossRefGoogle Scholar
  45. Korshunova, Y., et al., Massively parallel bisulphite pyrosequencing reveals the molecular complexity of breast cancer-associated cytosine-methylation patterns obtained from tissue and serum DNA. Genome Res, 2008. 18(1): 19–29.PubMedCrossRefGoogle Scholar
  46. Kremenskoy, M., et al., Genome-wide analysis of DNA methylation status of CpG islands in embryoid bodies, teratomas, and fetuses. Biochem Biophys Res Commun, 2003. 311(4): 884–90.PubMedCrossRefGoogle Scholar
  47. Kuang, S.Q., et al., Genome-wide identification of aberrantly methylated promoter associated CpG islands in acute lymphocytic leukemia. Leukemia, 2008.Google Scholar
  48. Laird, P.W., The power and the promise of DNA methylation markers. Nature Rev Cancer, 2003. 3(4): 253–66.CrossRefGoogle Scholar
  49. Lippman, Z., et al., Profiling DNA methylation patterns using genomic tiling microarrays. Nature Methods, 2005. 2(3): 219–24.PubMedCrossRefGoogle Scholar
  50. Maekita, T., et al., High levels of aberrant DNA methylation in Helicobacter pylori-infected gastric mucosae and its possible association with gastric cancer risk. Clin Cancer Res, 2006. 12(3 Pt 1): 989–95.PubMedCrossRefGoogle Scholar
  51. Matzke, M., et al., RNA-directed DNA methylation and Pol IVb in Arabidopsis. Cold Spring Harb Symp Quant Biol, 2006. 71: 449–59.PubMedCrossRefGoogle Scholar
  52. Meissner, A., et al., Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature, 2008.7;454(7205):766–70.CrossRefGoogle Scholar
  53. Meissner, A., et al., Reduced representation bisulfite sequencing for comparative high-resolution DNA methylation analysis. Nucleic Acids Res, 2005. 33(18): 5868–77.PubMedCrossRefGoogle Scholar
  54. Metivier, R., et al., Cyclical DNA methylation of a transcriptionally active promoter. Nature, 2008. 452(7183): 45–50.PubMedCrossRefGoogle Scholar
  55. Mikkelsen, T.S., et al., Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature, 2007. 448(7153): 553–60.PubMedCrossRefGoogle Scholar
  56. Morris, K.V., et al., Small interfering RNA-induced transcriptional gene silencing in human cells. Science, 2004. 305(5688): 1289–92.PubMedCrossRefGoogle Scholar
  57. Okitsu, C.Y. and C.L. Hsieh, DNA methylation dictates histone H3K4 methylation. Mol Cell Biol, 2007. 27(7): 2746–57.PubMedCrossRefGoogle Scholar
  58. Ooi, S.K. and T.H. Bestor, The colorful history of active DNA demethylation. Cell, 2008. 133(7): 1145–8.PubMedCrossRefGoogle Scholar
  59. Ooi, S.K., et al., DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature, 2007. 448(7154): 714–7.PubMedCrossRefGoogle Scholar
  60. Ordway, J.M., et al., Identification of novel high-frequency DNA methylation changes in breast cancer. PLoS ONE, 2007. 2(12): e1314.PubMedCrossRefGoogle Scholar
  61. Pfeifer, G.P., et al., In vivo footprint and methylation analysis by PCR-aided genomic sequencing: comparison of active and inactive X chromosomal DNA at the CpG island and promoter of human PGK-1. Genes Dev, 1990. 4(8): 1277–87.PubMedCrossRefGoogle Scholar
  62. Pikaard, C.S., Cell biology of the Arabidopsis nuclear siRNA pathway for RNA-directed chromatin modification. Cold Spring Harb Symp Quant Biol, 2006. 71: 473–80.PubMedCrossRefGoogle Scholar
  63. Reinders, J., et al., Genome-wide, high-resolution DNA methylation profiling using bisulfite-mediated cytosine conversion. Genome Res, 2008. 18(3): 469–76.PubMedCrossRefGoogle Scholar
  64. Sarter, B., et al., Sex differential in methylation patterns of selected genes in Singapore Chinese. Hum Genet, 2005. 117(4): 402–3.PubMedCrossRefGoogle Scholar
  65. Schilling, E. and M. Rehli, Global, comparative analysis of tissue-specific promoter CpG methylation. Genomics, 2007 90(3): 314–23.PubMedCrossRefGoogle Scholar
  66. Selker, E.U., Genome defense and DNA methylation in Neurospora. Cold Spring Harb Symp Quant Biol, 2004. 69: 119–24.PubMedCrossRefGoogle Scholar
  67. Shen, L., et al., Genome-wide profiling of DNA methylation reveals a class of normally methylated CpG island promoters. PLoS Genet, 2007. 3(10): 2023–36.PubMedCrossRefGoogle Scholar
  68. Shiota, K., DNA methylation profiles of CpG islands for cellular differentiation and development in mammals. Cytogenet Genome Res, 2004. 105(2–4): 325–34.PubMedCrossRefGoogle Scholar
  69. Smallwood, A., et al., Functional cooperation between HP1 and DNMT1 mediates gene silencing. Genes Dev, 2007. 21(10): 1169–78.PubMedCrossRefGoogle Scholar
  70. Smith, J.F., et al., Identification of DNA Methylation in 3’ Genomic Regions that are Associated with Upregulation of Gene Expression in Colorectal Cancer. Epigenetics, 2007. 2(3).Google Scholar
  71. Song, F., et al., Association of tissue-specific differentially methylated regions (TDMs) with differential gene expression. Proc Natl Acad Sci USA, 2005. 102(9): 3336–41.PubMedCrossRefGoogle Scholar
  72. Spitz, F., F. Gonzalez, and D. Duboule, A global control region defines a chromosomal regulatory landscape containing the HoxD cluster. Cell, 2003. 113(3): 405–17.PubMedCrossRefGoogle Scholar
  73. Srinivasan, P.R., Kinetics of incorporation of 5-methylcytosine in HeLa cells. Biochim Biophys Acta, 1962. 55: 553–6.PubMedCrossRefGoogle Scholar
  74. Strahl, B.D. and C.D. Allis, The language of covalent histone modifications. Nature, 2000. 403(6765): 41–5.PubMedCrossRefGoogle Scholar
  75. Suter, C.M., D.I. Martin, and R.L. Ward, Germline epimutation of MLH1 in individuals with multiple cancers. Nature Genet, 2004. 36(5): 497–501.PubMedCrossRefGoogle Scholar
  76. Suzuki, M.M. and A. Bird, DNA methylation landscapes: provocative insights from epigenomics. Nature Rev Genet, 2008. 9(6): 465–76.CrossRefPubMedGoogle Scholar
  77. Suzuki, M.M., et al., CpG methylation is targeted to transcription units in an invertebrate genome. Genome Res, 2007. 17(5): 625–31.PubMedCrossRefGoogle Scholar
  78. Taylor, K.H., et al., Ultradeep bisulfite sequencing analysis of DNA methylation patterns in multiple gene promoters by 454 sequencing. Cancer Res, 2007. 67(18): 8511–8.PubMedCrossRefGoogle Scholar
  79. The ENCODE Project Consortium, Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature, 2007. 447(7146): 799–816.CrossRefGoogle Scholar
  80. Trinh, B.N., T.I. Long, and P.W. Laird, DNA methylation analysis by MethyLight technology. Methods, 2001. 25(4): 456–62.PubMedCrossRefGoogle Scholar
  81. Vire, E., et al., The Polycomb group protein EZH2 directly controls DNA methylation. Nature, 2006. 439(7078): 871–4.PubMedCrossRefGoogle Scholar
  82. Walsh, C.P. and T.H. Bestor, Cytosine methylation and mammalian development. Genes Dev, 1999. 13(1): 26–34.PubMedCrossRefGoogle Scholar
  83. Waterland, R.A. and R.L. Jirtle, Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol, 2003. 23(15): 5293–300.PubMedCrossRefGoogle Scholar
  84. Waterland, R.A., Assessing the effects of high methionine intake on DNA methylation. J Nutr, 2006. 136(6 Suppl): 1706S-1710S.PubMedGoogle Scholar
  85. Weber, M., et al., Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells. Nat Genet, 2005. 37(8): 853–62.PubMedCrossRefGoogle Scholar
  86. Weber, M., et al., Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nature Genet, 2007. 39(4): 457–66.PubMedCrossRefGoogle Scholar
  87. Zilberman, D. and S. Henikoff, Genome-wide analysis of DNA methylation patterns. Development, 2007 134(22): 3959–65.Google Scholar
  88. Zilberman, D., et al., Genome-wide analysis of Arabidopsis thaliana DNA methylation uncovers an interdependence between methylation and transcription. Nature Genet, 2007. 39(1): 61–9.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • J.M. Greally
    • 1
  1. 1.Einstein Center for Epigenomics, Department of Genetics Albert Einstein College of MedicineBronx

Personalised recommendations