Cancer epigenomics: DNA methylomes and histone-modification maps

Key Points

  • During the past two decades, an increasing amount of experimental data has been gathered that support the idea that epigenetic alterations, particularly DNA methylation and histone modifications, have a crucial role in the development and progression of human cancer.

  • The epigenetic silencing of tumour-suppressor genes by CpG-island-promoter hypermethylation has emerged as a driving force in tumorigenesis. Further investigations are required to understand the contributions of genomic DNA hypomethylation and altered histone-modification signatures in human tumours.

  • Epigenetic research is moving on from candidate-gene approaches towards genome-wide analyses, on the basis of the combination of new techniques combining bisulphite treatment and PCR, new antibodies against epigenetic marks and the epigenetic machinery, and high-resolution microarray platforms.

  • These new epigenomic analyses show a profound disruption of the epigenetic modifications of cancer cells, with a large number of genes undergoing methylation-associated silencing, a global change in the acetylation and methylation profiles of histones, and aberrations in the genes responsible for the maintenance of normal chromatin structure.

  • Epigenomic technologies have promising translational applications for human cancer, with potential for early diagnosis, prognosis and clinical management, particularly in the young field of pharmacoepigenetics.

  • Our knowledge of cancer epigenetics will benefit greatly from the development of ambitious whole-genome endeavours, such as the international consortia that have been set up for the analysis of complete human and model-organism epigenomes.

Abstract

An altered pattern of epigenetic modifications is central to many common human diseases, including cancer. Many studies have explored the mosaic patterns of DNA methylation and histone modification in cancer cells on a gene-by-gene basis; among their results has been the seminal finding of transcriptional silencing of tumour-suppressor genes by CpG-island-promoter hypermethylation. However, recent technological advances are now allowing cancer epigenetics to be studied genome-wide — an approach that has already begun to provide both biological insight and new avenues for translational research. It is time to 'upgrade' cancer epigenetics research and put together an ambitious plan to tackle the many unanswered questions in this field using epigenomics approaches.

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Figure 1: Altered DNA-methylation patterns in tumorigenesis.
Figure 2: Techniques for studying epigenetic changes in cancer.
Figure 3: Methods for profiling genome-wide DNA-methylation patterns.
Figure 4: Histone-modification maps for a typical chromosome in normal and cancer cells.

References

  1. 1

    Herman, J. G. & Baylin, S. B. Gene silencing in cancer in association with promoter hypermethylation. N. Engl. J. Med. 349, 2042–2054 (2003).

    CAS  Article  Google Scholar 

  2. 2

    Feinberg, A. P. & Tycko, B. The history of cancer epigenetics. Nature Rev. Cancer 4, 143–153 (2004).

    CAS  Article  Google Scholar 

  3. 3

    Egger, G., Liang, G., Aparicio, A. & Jones, P. A. Epigenetics in human disease and prospects for epigenetic therapy. Nature 429, 457–463 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4

    Esteller, M. Aberrant DNA methylation as a cancer-inducing mechanism. Annu. Rev. Pharmacol. Toxicol. 45, 629–656 (2005).

    CAS  Article  Google Scholar 

  5. 5

    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  Article  PubMed  PubMed Central  Google Scholar 

  6. 6

    Fahrner, J. A., Eguchi, S., Herman, J. G. & Baylin, S. B. Dependence of histone modifications and gene expression on DNA hypermethylation in cancer. Cancer Res. 62, 7213–7218 (2002).

    CAS  Google Scholar 

  7. 7

    Ballestar, E. et al. Methyl-CpG binding proteins identify novel sites of epigenetic inactivation in human cancer. EMBO J. 22, 6335–6345 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8

    Fraga, M. F. et al. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nature Genet. 37, 391–400 (2005). The first report of a common disruption of histone- modification patterns in cancer cells.

    CAS  Article  Google Scholar 

  9. 9

    Pruitt, K. et al. Inhibition of SIRT1 reactivates silenced cancer genes without loss of promoter DNA hypermethylation. PLoS Genet. 2, e40 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11

    Walsh, C. P., Chaillet, J. R. & Bestor, T. H. Transcription of IAP endogenous retroviruses is constrained by cytosine methylation. Nature Genet. 20, 116–117 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12

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

    CAS  Article  Google Scholar 

  13. 13

    Esteller, M. & Almouzni, G. How epigenetics integrates nuclear functions. Workshop on epigenetics and chromatin: transcriptional regulation and beyond. EMBO Rep. 6, 624–628 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14

    Reik, W. & Lewis, A. Co-evolution of X-chromosome inactivation and imprinting in mammals. Nature Rev. Genet. 6, 403–410 (2005).

    CAS  Article  Google Scholar 

  15. 15

    Bodey, B. Cancer-testis antigens: promising targets for antigen directed antineoplastic immunotherapy. Expert Opin. Biol. Ther. 2, 577–584 (2002).

    CAS  Article  Google Scholar 

  16. 16

    Futscher, B. W. et al. Role for DNA methylation in the control of cell type specific maspin expression. Nature Genet. 31, 175–179 (2002).

    CAS  Article  Google Scholar 

  17. 17

    Kaneda, A. & Feinberg, A. P. Loss of imprinting of IGF2: a common epigenetic modifier of intestinal tumor risk. Cancer Res. 65, 11236–11240 (2005).

    CAS  Article  Google Scholar 

  18. 18

    Wade, P. A. Methyl CpG-binding proteins and transcriptional repression. BioEssays 23, 1131–1137 (2001).

    CAS  Article  Google Scholar 

  19. 19

    Dobosy, J. R. & Selker, E. U. Emerging connections between DNA methylation and histone acetylation. Cell. Mol. Life Sci. 58, 721–727 (2001).

    CAS  Article  Google Scholar 

  20. 20

    Wang, Y. et al. Beyond the double helix: writing and reading the histone code. Novartis Found. Symp. 259, 3–17 (2004).

    CAS  Google Scholar 

  21. 21

    Sanders, S. L. et al. Methylation of histone H4 lysine 20 controls recruitment of Crb2 to sites of DNA damage. Cell 119, 603–614 (2004).

    CAS  Article  Google Scholar 

  22. 22

    Espada, J. et al. Human DNA methyltransferase 1 is required for maintenance of the histone H3 modification pattern. J. Biol. Chem. 279, 37175–37184 (2004).

    CAS  Article  Google Scholar 

  23. 23

    Seligson, D. B. et al. Global histone modification patterns predict risk of prostate cancer recurrence. Nature 435, 1262–1266 (2005). The first profile of histone modifications in cancer with prognostic relevance.

    CAS  Article  Google Scholar 

  24. 24

    Barbacid, M. ras genes. Annu. Rev. Biochem. 56, 779–827 (1987).

    CAS  Article  Google Scholar 

  25. 25

    Fraga, M. F. & Esteller, M. DNA methylation: a profile of methods and applications. Biotechniques 33, 632–649 (2002).

    CAS  Article  Google Scholar 

  26. 26

    Clark, S. J., Harrison, J., Paul, C. L. & Frommer, M. High sensitivity mapping of methylated cytosines. Nucleic Acids Res. 22, 2990–2997 (1994).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27

    Herman, J. G. et al. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc. Natl Acad. Sci. USA 93, 9821–9826 (1996).

    CAS  Article  Google Scholar 

  28. 28

    Eads, C. A. et al. MethyLight: a high-throughput assay to measure DNA methylation. Nucleic Acids Res. 28, e32 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29

    Uhlmann, K. et al. Evaluation of a potential epigenetic biomarker by quantitative methyl-single nucleotide polymorphism analysis. Electrophoresis 23, 4072–4079 (2002).

    CAS  Article  Google Scholar 

  30. 30

    Costello, J. F. et al. Aberrant CpG-island methylation has non-random and tumour-type-specific patterns. Nature Genet. 24, 132–138 (2000). One of the first studies to define the number of hypermethylated CpG islands in cancer cells and their distribution according to tumour type.

    CAS  Article  Google Scholar 

  31. 31

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

    CAS  Article  Google Scholar 

  32. 32

    Welsh, J. & McClelland, M. Fingerprinting genomes using PCR with arbitrary primers. Nucleic Acids Res. 18, 7213–7218 (1990).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33

    Gonzalgo, M. L. et al. Identification and characterization of differentially methylated regions of genomic DNA by methylation-sensitive arbitrarily primed PCR. Cancer Res. 57, 594–599 (1997).

    CAS  Google Scholar 

  34. 34

    Toyota, M. et al. Identification of differentially methylated sequences in colorectal cancer by methylated CpG island amplification. Cancer Res. 59, 2307–2312 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Frigola, J., Ribas, M., Risques, R. A. & Peinado, M. A. Methylome profiling of cancer cells by amplification of inter-methylated sites (AIMS). Nucleic Acids Res. 30, e28 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  36. 36

    Huang, T. H., Perry, M. R. & Laux, D. E. Methylation profiling of CpG islands in human breast cancer cells. Hum. Mol. Genet. 8, 459–470 (1999).

    CAS  Article  Google Scholar 

  37. 37

    Khulan, B. et al. Comparative isoschizomer profiling of cytosine methylation: the HELP assay. Genome Res. 16, 1046–1055 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38

    Lopez-Serra, L. et al. A profile of MBD protein occupancy of hypermethylated promoter CpG islands of tumor suppressor genes in human cancer. Cancer Res. 66, 8342–8346 (2006).

    CAS  Article  Google Scholar 

  39. 39

    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). The first report of the use of methyl-DIP, a powerful epigenomic technique for identifying DNA-methylation changes in transformed cells.

    CAS  Article  Google Scholar 

  40. 40

    Keshet, I. et al. Evidence for an instructive mechanism of de novo methylation in cancer cells. Nature Genet. 38, 149–153 (2006). This paper reports extensive mapping of DNA-methylation changes in cancer cells using methyl-DIP.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41

    Zhang, X. et al. Genome-wide high-resolution mapping and functional analysis of DNA methylation in Arabidopsis. Cell 126, 1189–1201 (2006). A ground-breaking study that combines methyl-DIP and tiling arrays, providing the first example of an almost complete DNA methylome in one organism.

    CAS  Article  Google Scholar 

  42. 42

    Suzuki, H. et al. A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer. Nature Genet. 31, 141–149 (2002).

    CAS  Article  Google Scholar 

  43. 43

    Yamashita, K. et al. Pharmacologic unmasking of epigenetically silenced tumor suppressor genes in esophageal squamous cell carcinoma. Cancer Cell 2, 485–495 (2002). References 42 and 43 describe pioneering studies that combine DNA-demethylating agents and expression microarrays to reveal methylation-associated silencing in cancer cells.

    CAS  Article  Google Scholar 

  44. 44

    Fraga, M. F. et al. A mouse skin multistage carcinogenesis model reflects the aberrant DNA methylation patterns of human tumors. Cancer Res. 64, 5527–5534 (2004).

    CAS  Article  Google Scholar 

  45. 45

    O'Neill, L. P., Vermilyea, M. D. & Turner, B. M. Epigenetic characterization of the early embryo with a chromatin immunoprecipitation protocol applicable to small cell populations. Nature Genet. 38, 835–841 (2006).

    CAS  Article  Google Scholar 

  46. 46

    Lippman, Z. et al. Role of transposable elements in heterochromatin and epigenetic control. Nature 430, 471–476 (2004).

    CAS  Article  Google Scholar 

  47. 47

    Kurdistani, S. K., Tavazoie, S. & Grunstein, M. Mapping global histone acetylation patterns to gene expression. Cell 117, 721–733 (2004). A pioneering study in which histone-modification changes in yeast were analysed by ChIP-on-chip.

    CAS  Article  Google Scholar 

  48. 48

    Pokholok, D. K. et al. Genome-wide map of nucleosome acetylation and methylation in yeast. Cell 122, 517–527 (2005).

    CAS  Article  PubMed  Google Scholar 

  49. 49

    Schubeler, D. et al. The histone modification pattern of active genes revealed through genome-wide chromatin analysis of a higher eukaryote. Genes Dev. 18, 1263–1271 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  50. 50

    Martens, J. H. et al. The profile of repeat-associated histone lysine methylation states in the mouse epigenome. EMBO J. 24, 800–812 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. 51

    Bernstein, B. E. et al. Genomic maps and comparative analysis of histone modifications in human and mouse. Cell 120, 169–181 (2005).

    CAS  Article  Google Scholar 

  52. 52

    Bernstein, B. E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315–326 (2006).

    CAS  Article  Google Scholar 

  53. 53

    Azuara, V. et al. Chromatin signatures of pluripotent cell lines. Nature Cell Biol. 8, 532–538 (2006).

    CAS  Article  Google Scholar 

  54. 54

    Yu, L. et al. Global assessment of promoter methylation in a mouse model of cancer identifies ID4 as a putative tumor-suppressor gene in human leukemia. Nature Genet. 37, 265–274 (2005).

    CAS  Article  Google Scholar 

  55. 55

    Esteller, M., Corn, P. G., Baylin, S. B. & Herman, J. G. A gene hypermethylation profile of human cancer. Cancer Res. 8, 3225–3229 (2001). The most comprehensive analysis of promoter CpG-island hypermethylation in human cancer using a candidate-gene approach.

    Google Scholar 

  56. 56

    Paz, M. F. et al. A systematic profile of DNA methylation in human cancer cell lines. Cancer Res. 63, 1114–1121 (2003).

    CAS  Google Scholar 

  57. 57

    Sjoblom, T. et al. The consensus coding sequences of human breast and colorectal cancers. Science 314, 268–274 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Paz, M. F. et al. Genetic unmasking of epigenetically silenced tumor suppressor genes in colon cancer cells deficient in DNA methyltransferases. Hum. Mol. Genet. 12, 2209–2219 (2003).

    CAS  Article  Google Scholar 

  59. 59

    Saito, Y. et al. Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatin-modifying drugs in human cancer cells. Cancer Cell 9, 435–443 (2006).

    CAS  Article  Google Scholar 

  60. 60

    Lujambio, A. et al. Genetic unmasking of an epigenetically silenced microRNA in human cancer cells. Cancer Res. 67, 1424–1429 (2007). References 59 and 60 describe the first examples of CpG-island methylation-associated silencing of microRNAs in human cancer.

    CAS  Article  Google Scholar 

  61. 61

    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 (2006).

    Article  CAS  Google Scholar 

  62. 62

    Widschwendter, M. et al. Epigenetic stem cell signature in cancer. Nature Genet. 39, 157–158 (2006).

    Article  CAS  Google Scholar 

  63. 63

    Di Croce, L. et al. Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science 295, 1079–1082 (2002).

    CAS  Article  Google Scholar 

  64. 64

    Esteller, M. et al. Cancer epigenetics and methylation. Science 297, 1807–1808 (2002).

    Article  Google Scholar 

  65. 65

    Brenner, C. et al. Myc represses transcription through recruitment of DNA methyltransferase corepressor. EMBO J. 24, 336–346 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. 66

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. 67

    Richon, V. M., Sandhoff, T. W., Rifkind R. A. & Marks, P. A. Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc. Natl Acad. Sci. USA 97, 10014–10019 (2000).

    CAS  Article  Google Scholar 

  68. 68

    Esteller, M. & Herman, J. G. Generating mutations but providing chemosensitivity: the role of O6-methylguanine DNA methyltransferase in human cancer. Oncogene 23, 1–8 (2004).

    CAS  Article  Google Scholar 

  69. 69

    Tryndyak, V. P., Kovalchuk, O. & Pogribny, I. P. Loss of DNA methylation and histone H4 lysine 20 trimethylation in human breast cancer cells is associated with aberrant expression of DNA methyltransferase 1, Suv4–20h2 histone methyltransferase and methyl-binding proteins. Cancer Biol. Ther. 5, 65–70 (2006).

    CAS  Article  Google Scholar 

  70. 70

    Pogribny, I. P. et al. Histone H3 lysine 9 and H4 lysine 20 trimethylation and the expression of Suv4–20h2 and Suv-39h1 histone methyltransferases in hepatocarcinogenesis induced by methyl deficiency in rats. Carcinogenesis 27, 1180–1186 (2006).

    CAS  Article  Google Scholar 

  71. 71

    Jacobsen, S. E. & Meyerowitz, E. M. Hypermethylated SUPERMAN epigenetic alleles in Arabidopsis. Science 277, 1100–1103 (1997).

    CAS  Article  Google Scholar 

  72. 72

    Mager, J. & Bartolomei, M. S. Strategies for dissecting epigenetic mechanisms in the mouse. Nature Genet. 37, 1194–1200 (2005).

    CAS  Article  Google Scholar 

  73. 73

    Ozdag, H. et al. Differential expression of selected histone modifier genes in human solid cancers. BMC Genomics 7, 90 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Yang, X. J. The diverse superfamily of lysine acetyltransferases and their roles in leukemia and other diseases. Nucleic Acids Res. 32, 959–976 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  75. 75

    Moore, S. D. et al. Uterine leiomyomata with t(10;17) disrupt the histone acetyltransferase MORF. Cancer Res. 64, 5570–5577 (2004).

    CAS  Article  Google Scholar 

  76. 76

    Peters, A. H. et al. Loss of the Suv39h histone methyltransferases impairs mammalian heterochromatin and genome stability. Cell 107, 323–337 (2001).

    CAS  Article  Google Scholar 

  77. 77

    Ropero, S. et al. A truncating mutation of HDAC2 in human cancers confers resistance to histone deacetylase inhibition. Nature Genet. 38, 566–569 (2006). The first-described disruption of a histone deacetylase in human cancer provides a basis for further pharmacogenomic studies.

    CAS  Article  Google Scholar 

  78. 78

    Varmus, H. & Stillman, B. Support for the Human Cancer Genome Project. Science 310, 1615 (2005).

    CAS  Article  Google Scholar 

  79. 79

    Lee, W. H. et al. Cytidine methylation of regulatory sequences near the pi-class glutathione S-transferase gene accompanies human prostatic carcinogenesis. Proc. Natl Acad. Sci. USA 91, 11733–11737 (1994).

    CAS  Article  Google Scholar 

  80. 80

    Cairns, P. et al. Molecular detection of prostate cancer in urine by GSTP1 hypermethylation. Clin. Cancer Res. 7, 2727–2730 (2001).

    CAS  Google Scholar 

  81. 81

    Laird, P. W. The power and the promise of DNA methylation markers. Nature Rev. Cancer 3, 253–266 (2003).

    CAS  Article  Google Scholar 

  82. 82

    Baylin, S. B. & Ohm, J. E. Epigenetic gene silencing in cancer — a mechanism for early oncogenic pathway addiction? Nature Rev. Cancer 6, 107–116 (2006).

    CAS  Article  Google Scholar 

  83. 83

    Gallagher, W. M. et al. Multiple markers for melanoma progression regulated by DNA methylation: insights from transcriptomic studies. Carcinogenesis 26, 1856–1867 (2005).

    CAS  Article  Google Scholar 

  84. 84

    Esteller, M. et al. DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis. Hum. Mol. Genet. 10, 3001–3007 (2001).

    CAS  Article  Google Scholar 

  85. 85

    Alaminos, M. et al. Clustering of gene hypermethylation associated with clinical risk groups in neuroblastoma. J. Natl Cancer Inst. 96, 1208–1219 (2004).

    CAS  Article  Google Scholar 

  86. 86

    Tsou, J. A. et al. Distinct DNA methylation profiles in malignant mesothelioma, lung adenocarcinoma, and non-tumor lung. Lung Cancer 47, 193–204 (2005).

    Article  Google Scholar 

  87. 87

    Wei, S. H. et al. Prognostic DNA methylation biomarkers in ovarian cancer. Clin. Cancer Res. 12, 2788–2794 (2006).

    CAS  Article  Google Scholar 

  88. 88

    Esteller, M. et al. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N. Engl. J. Med. 343, 1350–1354 (2000). The first translational use of a hypermethylated CpG island in the management of cancer patients.

    CAS  Article  Google Scholar 

  89. 89

    Hegi, M. E. et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N. Engl. J. Med. 352, 997–1003 (2005).

    CAS  Article  Google Scholar 

  90. 90

    Esteller, M. et al. Hypermethylation of the DNA repair gene O(6)-methylguanine DNA methyltransferase and survival of patients with diffuse large B-cell lymphoma. J. Natl Cancer Inst. 94, 26–32 (2002).

    CAS  Article  Google Scholar 

  91. 91

    Glasspool, R. M., Teodoridis, J. M. & Brown, R. Epigenetics as a mechanism driving polygenic clinical drug resistance. Br. J. Cancer 94, 1087–1092 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  92. 92

    Mack, G. S. Epigenetic cancer therapy makes headway. J. Natl Cancer Inst. 98, 1443–1444 (2006).

    Article  Google Scholar 

  93. 93

    Thompson, C. A. Vorinostat approved for rare lymphoma. Am. J. Health Syst. Pharm. 63, 2168 (2006).

    Google Scholar 

  94. 94

    Seo, S. & Kroll, K. L. Geminin's double life: chromatin connections that regulate transcription at the transition from proliferation to differentiation. Cell Cycle 5, 374–379 (2006).

    CAS  Article  Google Scholar 

  95. 95

    Jones, P. A. & Martienssen, R. A blueprint for a Human Epigenome Project: the AACR Human Epigenome Workshop. Cancer Res. 65, 11241–11246 (2005).

    CAS  Article  Google Scholar 

  96. 96

    Rauscher, F. J. It is time for a Human Epigenome Project. Cancer Res. 65, 11229 (2005).

    CAS  Article  Google Scholar 

  97. 97

    Garber, K. Momentum building for Human Epigenome Project. J. Natl Cancer Inst. 98, 84–86 (2006).

    Article  Google Scholar 

  98. 98

    Esteller, M. The necessity of a Human Epigenome Project. Carcinogenesis 27, 1121–1125 (2006).

    CAS  Article  Google Scholar 

  99. 99

    Zilberman, D. et al. Genome-wide analysis of Arabidopsis thaliana DNA methylation uncovers an interdependence between methylation and transcription. Nature Genet. 39, 61–69 (2006). A high-resolution map of the A . thaliana DNA methylome that addresses its relationship to gene-expression patterns.

    Article  CAS  Google Scholar 

  100. 100

    Rakian, V. K. et al. DNA methylation profiling of the human major histocompatibility complex: a pilot study for the Human Epigenome Project. PLoS Biol. 2, e405 (2004).

    Article  CAS  Google Scholar 

  101. 101

    Fraga, M. F. et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc. Natl Acad. Sci. USA 102, 10604–10609 (2005). A comprehensive epigenomic study that demonstrates the presence of DNA methylation and histone modifications in individuals who have the same genetic background.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  102. 102

    Frigola, J. et al. Epigenetic remodeling in colorectal cancer results in coordinate gene suppression across an entire chromosome band. Nature Genet. 38, 540–549 (2006).

    CAS  Article  Google Scholar 

  103. 103

    Stransky, N. et al. Regional copy number-independent deregulation of transcription in cancer. Nature Genet. 38, 1386–1396 (2006).

    CAS  Article  Google Scholar 

  104. 104

    Eckhardt, F. et al. DNA methylation profiling of human chromosomes 6, 20 and 22. Nature Genet. 38, 1378–1385 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

M.E. research is supported by the Science Department of the Spanish Government.

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Glossary

Endoparasitic sequences

Repeated sequences, most of which are derived from transposable elements. These sequences are propagated by inserting new copies of themselves into random sites in the genome.

Genomic imprinting

The epigenetic marking of a locus on the basis of parental origin, which results in monoallelic gene expression.

High-performance liquid chromatography

(HPLC). A technique for separating DNA or protein molecules by molecular weight and conformation. The molecules are resolved by differences in their distribution between a stationary phase and a mobile phase. The resolution is increased by increasing the pressure of the system.

High-performance capillary electrophoresis

(HPCE). A class of separation techniques that use narrow-bore fused-silica capillaries to separate a complex mixture of chemical compounds. Molecules are separated on the basis of differences in charge, size, structure and hydrophobic potential using strong electric fields.

Methylation-specific PCR

This DNA-methylation assay entails initial modification of DNA by sodium bisulphite, converting all unmethylated, but not methylated, cytosines to uracil, and subsequent amplification with primers that are specific for methylated versus unmethylated DNA.

Two-dimensional electrophoresis

A gel electrophoresis method in which the proteins in a sample are separated by their isoelectric points in one dimension, and by size in a second, perpendicular dimension.

MethyLight

A high-throughput quantitative methylation assay that uses fluorescence-based real-time PCR (TaqMan) technology and requires no further manipulations after the PCR step. This technique is carried out in combination with bisulphite treatment (in which unmethylated cytosine residues are converted to uracil), and sequence discrimination is achieved by designing the primers to overlap with potential sites of DNA methylation (CpG dinucleotides).

Pyrosequencing

A DNA-sequencing method in which light is emitted as a result of an enzymatic reaction, each time a nucleotide is incorporated into the growing DNA chain. As applied to methylation detection, methylation-dependent DNA sequence variation, which is achieved by sodium bisulphite treatment, is treated as a kind of SNP of the C–T type, and is subjected to conventional SNP typing.

Arbitrary primed PCR

Amplification of genomic DNA using arbitrary primers. The first amplification cycles are carried out at a low annealing temperature, such that the primer hybridizes to many non-specific sequences. The temperature is then increased, so that only the 'best' products of the initial annealing events are amplified further, generating a number of discrete bands that provide a fingerprint of the genome.

Amplification of intermethylated sites

(AIMS). A DNA-methylation fingerprinting technique that uses methyl-isoschizomers and arbitrary PCR amplification to obtain many anonymous bands, which represent DNA sequences flanked by two methylated sites.

Chromatin immunoprecipitation

(ChIP). The isolation, using specific antibodies, of chromatin fragments that are bound by a particular nuclear factor or associated with a particular histone-modification signature. The immunoprecipated DNA can subsequently be analysed with specific PCR primers.

ChIP-on-chip

A combination of chromatin immunoprecipitation with hybridization to genomic microarrays that is used to identify DNA sequences bound to a particular nuclear factor or with a specific histone-modification profile.

Methyl-DIP

(Methylated DNA immunoprecipitation).Immunoprecipitation with anti-5-methylcytosine antibodies followed by hybridization to genomic microarrays, allowing the identification of methyl-CpG-rich sequences.

Tiling microarrays

Microarrays that contain a set of overlapping oligonucleotides or other probes that span either the entire genome or, for a more specialized approach, a subregion of interest.

Mass spectrometry

An analytical technique determining molecular mass. This involves an ion source in which gas-phase molecular ions are produced from the analyte molecules, a mass analyser in which electrical and/or magnetic fields are used to separate the analyte ions by their different mass-to-charge ratios, and a detector for recording the separated ions.

Liquid chromatography–electrospray mass spectrometry

A mass spectrometry technique in which ionization of molecules is carried out within aerosols of small droplets. Molecules are then identified using electric and magnetic fields.

Tandem mass spectrometry

An analytical system in which two linked mass spectrometers are used to measure small amounts of metabolites. The analytes are separated according to their mass and charge. By programming the instrument to respond to only certain masses, a high degree of specificity and sensitivity can be achieved.

Adenoma

A cellular growth of glandular origin, which can arise from organs including the colon and the adrenal, pituitary and thyroid glands. These growths are benign, but some are known to have the potential, over time, to transform to malignancy (at which point they become known as adenocarcinoma.)

Prognostic dendogram

A tree diagram that represents the relative similarities among different samples corresponding to human patients in terms of outcome prediction. Samples clustering in the same branch of the dendrogram have the same prognostic markers (for example, age, stage, chromosomal deletions or gains, or specific gene expression) and are likely to have the same outcome.

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Esteller, M. Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet 8, 286–298 (2007). https://doi.org/10.1038/nrg2005

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