Genomic insights into cancer-associated aberrant CpG island hypermethylation

Briefings in Functional Genomics

Volumn 12, Issue 3, 2013, Pages 174-190

  Sproul, Duncan ^a   Meehan, Richard R ^a  

^a UNIVERSITY OF EDINBURGH   (United Kingdom)

Author keywords

Cancer; CpG islands; DNA methylation; Epigenetics; Epigenomics

Indexed keywords

BRCA1 PROTEIN; CALCITONIN; CHEMOKINE RECEPTOR CXCR4; CYCLIN DEPENDENT KINASE INHIBITOR 2A; DNA METHYLTRANSFERASE 1; DNA METHYLTRANSFERASE 3B; PROTEIN MLH1; TRANSCRIPTION FACTOR RUNX3; TRANSCRIPTION FACTOR SLUG; TRANSCRIPTION FACTOR SNAIL; TUMOR PROMOTER;

ARTICLE; CANCER CELL; CANCER GENETICS; CANCER SUSCEPTIBILITY; CARCINOGENESIS; CELL DIFFERENTIATION; CPG ISLAND; DNA METHYLATION; EPIGENETICS; GENE ACTIVATION; GENE INACTIVATION; GENE MUTATION; GENE SILENCING; GENETIC ASSOCIATION; GENETIC PREDISPOSITION; HETEROZYGOTE; HUMAN; METASTASIS; NONHUMAN; PROMOTER REGION; TRANSCRIPTION INITIATION; TUMOR SUPPRESSOR GENE;

CANCER; CPG ISLANDS; DNA METHYLATION; EPIGENETICS; EPIGENOMICS;

CPG ISLANDS; DNA METHYLATION; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; NEOPLASMS;

EID: 84878441665     PISSN: 20412649     EISSN: 20412657     Source Type: Journal    
DOI: 10.1093/bfgp/els063     Document Type: Article

References (183)

1. Bird A. Perceptions of epigenetics. Nature 2007;447:396-8.
2. You JS, Jones PA. Cancer genetics and epigenetics: two sides of the same coin?. Cancer Cell 2012;22:9-20.
3. Ziller MJ, Muller F, Liao J, et al. Genomic distribution and inter-sample variation of non-CpG methylation across human cell types. PLoS Genet 2011;7:e1002389.
4. Suzuki MM, Bird A. DNA methylation landscapes: provocative insights from epigenomics. Nat Rev Genet 2008;9: 465-76.
5. Illingworth RS, Gruenewald-Schneider U, Webb S, et al. Orphan CpG islands identify numerous conserved promoters in the mammalian genome. PLoS Genet 2010;6: e1001134.
6. Bird AP. DNA methylation and the frequency of CpG in animal DNA. Nucleic Acids Res 1980;8:1499-504.
7. Rideout WM, III, Coetzee GA, Olumi AF, et al. 5-Methylcytosine as an endogenous mutagen in the human LDL receptor and p53 genes. Science 1990;249: 1288-90.
8. Fournier A, Sasai N, Nakao M, et al. The role of methylbinding proteins in chromatin organization and epigenome maintenance. Brief Funct Genomics 2012;11:251-64.
9. Cedar H, Bergman Y. Programming of DNA methylation patterns. Annu Rev Biochem 2012;81:97-117.
10. Bock C, Beerman I, Lien WH, et al. DNA methylation dynamics during in vivo differentiation of blood and skin stem cells. Mol Cell 2012;47:633-47.
11. Deaton AM, Webb S, Kerr AR, et al. Cell type-specific DNA methylation at intragenic CpG islands in the immune system. GenomeRes 2011;21:1074-86.
12. Irizarry RA, Ladd-Acosta C, Wen B, et al. The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet 2009;41:178-86.
13. Ji H, Ehrlich LI, Seita J, et al. Comprehensive methylome map of lineage commitment from haematopoietic progenitors. Nature 2010;467:338-42.
14. Kriaucionis S, Heintz N. The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science 2009;324:929-30.
15. Nestor CE, Ottaviano R, Reddington J, et al. Tissue-type is a major modifier of the 5-hydroxymethylcytosine content of human genes. Genome Res 2012;22:467-77.
16. Ehrlich M. DNA hypomethylation in cancer cells. Epigenomics 2009;1:239-59.
17. Wild L, Flanagan JM. Genome-wide hypomethylation in cancer may be a passive consequence of transformation. Biochim Biophys Acta 2010;1806:50-7.
18. Berman BP, Weisenberger DJ, Aman JF, et al. Regions of focal DNA hypermethylation and long-range hypomethylation in colorectal cancer coincide with nuclear lamina-associated domains. Nat Genet 2011;44:40-6.
19. Hon GC, Hawkins RD, Caballero OL, et al. Global DNA hypomethylation coupled to repressive chromatin domain formation and gene silencing in breast cancer. Genome Res 2012;22:246-58.
20. Haffner MC, Chaux A, Meeker AK, et al. Global 5-hydroxymethylcytosine content is significantly reduced in tissue stem/progenitor cell compartments and in human cancers. Oncotarget 2011;2:627-37.
21. Jin SG, Jiang Y, Qiu R, et al. 5-Hydroxymethylcytosine is strongly depleted in human cancers but its levels do not correlate with IDH1 mutations. Cancer Res 2011;71: 7360-5.
22. Lian CG, Xu Y, Ceol C, et al. Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma. Cell 2012;150:1135-46.
23. Boyes J, Bird A. Repression of genes by DNA methylation depends on CpG density and promoter strength: evidence for involvement of a methyl-CpG binding protein. EMBOJ 1992;11:327-33.
24. Feinberg AP, Tycko B. The history of cancer epigenetics. Nat Rev Cancer 2004;4:143-53.
25. Weinberg RA. The Biology of Cancer. New York: Garland Science, 2007.
26. Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N EnglJMed 2003;349:2042-54.
27. Greger V, Debus N, Lohmann D, et al. Frequency and parental origin of hypermethylated RB1 alleles in retinoblastoma. Hum Genet 1994;94:491-6.
28. Greger V, Passarge E, Hopping W, et al. Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma. Hum Genet 1989;83: 155-8.
29. Ohtani-Fujita N, Fujita T, Aoike A, et al. CpG methylation inactivates the promoter activity of the human retinoblastoma tumor-suppressor gene. Oncogene 1993;8: 1063-7.
30. Sakai T, Toguchida J, Ohtani N, et al. Allele-specific hypermethylation of the retinoblastoma tumor-suppressor gene. AmJHum Genet 1991;48:880-8.
31. Cunningham JM, Christensen ER, Tester DJ, et al. Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Res 1998;58: 3455-60.
32. Herman JG, Umar A, Polyak K, et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA 1998;95: 6870-5.
33. Esteller M, Silva JM, Dominguez G, et al. Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. JNatl Cancer Inst 2000;92:564-9.
34. Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. NatMed 2004;10:789-99.
35. Esteller M, Fraga MF, Guo M, et al. DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis. HumMol Genet 2001;10:3001-7.
36. Myohanen SK, Baylin SB, Herman JG. Hypermethylation can selectively silence individual p16ink4A alleles in neoplasia. Cancer Res 1998;58:591-3.
37. Ohtani-Fujita N, Dryja TP, Rapaport JM, et al. Hypermethylation in the retinoblastoma gene is associated with unilateral, sporadic retinoblastoma. Cancer Genet Cytogenet 1997;98:43-9.
38. Dworkin AM, Spearman AD, Tseng SY, et al. Methylation not a frequent "second hit" in tumors with germline BRCA mutations. Fam Cancer 2009;8:339-46.
39. Tung N, Miron A, Schnitt SJ, et al. Prevalence and predictors of loss of wild type BRCA1 in estrogen receptor positive and negative BRCA1-associated breast cancers. Breast Cancer Res 2010;12:R95.
40. Sproul D, Kitchen RR, Nestor CE, et al. Tissue of origin determines cancer-associated CpG island promoter hypermethylation patterns. Genome Biol 2012;13:R84.
41. Herman JG, Latif F, Weng Y, et al. Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. ProcNatl Acad SciUSA 1994;91:9700-4.
42. Hitchins MP, Rapkins RW, Kwok CT, et al. Dominantly inherited constitutional epigenetic silencing of MLH1 in a cancer-affected family is linked to a single nucleotide variant within the 50UTR. Cancer Cell 2011;20:200-13.
43. Ligtenberg MJ, Kuiper RP, Chan TL, et al. Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 30 exons of TACSTD1. Nat Genet 2009;41:112-7.
44. Turner N, Tutt A, Ashworth A. Hallmarks of 'BRCAness' in sporadic cancers. Nat Rev Cancer 2004;4:814-9.
45. Stratton MR. Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases. Breast Cancer Linkage Consortium. Lancet 1997;349:1505-10.
46. Weigelt B, Geyer FC, Reis-Filho JS. Histological types of breast cancer: how special are they?. Mol Oncol 2010;4: 192-208.
47. Turner NC, Reis-Filho JS, Russell AM, et al. BRCA1 dysfunction in sporadic basal-like breast cancer. Oncogene 2007; 26:2126-32.
48. Matros E, Wang ZC, Lodeiro G, et al. BRCA1 promoter methylation in sporadic breast tumors: relationship to gene expression profiles. Breast Cancer Res Treat 2005;91: 179-86.
49. TCGA. Integrated genomic analyses of ovarian carcinoma. Nature 2011;474:609-15.
50. Hammerman PS, Hayes DN, Wilkerson MD, et al. Comprehensive genomic characterization of squamous cell lung cancers. Nature 2012;489:519-25.
51. Patel K, Dickson J, Din S, et al. Targeting of 5-aza-20-deoxycytidine residues by chromatin-associated DNMT1 induces proteasomal degradation of the free enzyme. Nucleic Acids Res 2010;38:4313-24.
52. Veigl ML, Kasturi L, Olechnowicz J, et al. Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. Proc Natl Acad Sci USA 1998;95:8698-702.
53. Veeck J, Ropero S, Setien F, et al. BRCA1 CpG island hypermethylation predicts sensitivity to poly(adenosine diphosphate)-ribose polymerase inhibitors. J Clin Oncol 2010;28:e563-4, author reply e565-6.
54. Robert MF, Morin S, Beaulieu N, etal. DNMT1 is required to maintain CpG methylation and aberrant gene silencing in human cancer cells. Nat Genet 2003;33:61-5.
55. Rhee I, Bachman KE, Park BH, et al. DNMT1 and DNMT3b cooperate to silence genes in human cancer cells. Nature 2002;416:552-6.
56. Mohandas T, Sparkes RS, Shapiro LJ. Reactivation of an inactive human X chromosome: evidence for X inactivation by DNA methylation. Science 1981;211:393-6.
57. Lock LF, Takagi N, Martin GR. Methylation of the Hprt gene on the inactive X occurs after chromosome inactivation. Cell 1987;48:39-46.
58. Okamoto I, Heard E. Lessons from comparative analysis of X-chromosome inactivation in mammals. Chromosome Res 2009;17:659-69.
59. Sado T, Fenner MH, Tan SS, et al. X inactivation in the mouse embryo deficient for Dnmt1: distinct effect of hypomethylation on imprinted and random X inactivation. Dev Biol 2000;225:294-303.
60. Sado T, Okano M, Li E, etal. De novo DNA methylation is dispensable for the initiation and propagation of X chromosome inactivation. Development 2004;131:975-82.
61. Bestor TH. Unanswered questions about the role of promoter methylation in carcinogenesis. AnnNYAcadSci 2003; 983:22-7.
62. Clark SJ, Melki J. DNA methylation and gene silencing in cancer: which is the guilty party?. Oncogene 2002;21:5380-7.
63. Deaton AM, Bird A. CpG islands and the regulation of transcription. Genes Dev 2011;25:1010-22.
64. Fearon ER. BRCA1 and E-cadherin promoter hypermethylation and gene inactivation in cancer-association or mechanism?. JNatl Cancer Inst 2000;92:515-7.
65. Levanon D, Bernstein Y, Negreanu V, et al. Absence of Runx3 expression in normal gastrointestinal epithelium calls into question its tumour suppressor function. EMBO MolMed 2011;3:593-604.
66. Baylin SB, Hoppener JW, de Bustros A, et al. DNA methylation patterns of the calcitonin gene in human lung cancers and lymphomas. Cancer Res 1986;46:2917-22.
67. Costello JF, Fruhwald MC, Smiraglia DJ, et al. Aberrant CpG-island methylation has non-random and tumourtype- specific patterns. Nat Genet 2000;24:132-8.
68. Toyota M, Ahuja N, Ohe-Toyota M, et al. CpG island methylator phenotype in colorectal cancer. Proc Natl Acad SciUSA 1999;96:8681-6.
69. Fang F, Turcan S, Rimner A, et al. Breast cancer methylomes establish an epigenomic foundation for metastasis. Sci TranslMed 2011;3:75ra25.
70. Figueroa ME, Abdel-Wahab O, Lu C, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 2010;18:553-67.
71. Noushmehr H, Weisenberger DJ, Diefes K, et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 2010;17: 510-22.
72. Teodoridis JM, Hardie C, Brown R. CpG island methylator phenotype (CIMP) in cancer: causes and implications. Cancer Lett 2008;268:177-86.
73. Welch JS, Ley TJ, Link DC, et al. The origin and evolution of mutations in acute myeloid leukemia. Cell 2012;150: 264-78.
74. Antequera F, Boyes J, Bird A. High levels of de novo methylation and altered chromatin structure at CpG islands in cell lines. Cell 1990;62:503-14.
75. Sproul D, Nestor C, Culley J, et al. Transcriptionally repressed genes become aberrantly methylated and distinguish tumors of different lineages in breast cancer. Proc Natl Acad SciUSA 2011;108:4364-9.
76. Hinoue T, Weisenberger DJ, Lange CP, etal. Genome-scale analysis of aberrant DNA methylation in colorectal cancer. Genome Res 2012;22:271-82.
77. Houshdaran S, Hawley S, Palmer C, etal. DNA methylation profiles of ovarian epithelial carcinoma tumors and cell lines. PLoS One 2010;5:e9359.
78. Keshet I, Schlesinger Y, Farkash S, et al. Evidence for an instructive mechanism of de novo methylation in cancer cells. Nat Genet 2006;38:149-53.
79. O'Riain C, O'Shea DM, Yang Y, et al. Array-based DNA methylation profiling in follicular lymphoma. Leukemia 2009;23:1858-66.
80. Pike BL, Greiner TC, Wang X, et al. DNA methylation profiles in diffuse large B-cell lymphoma and their relationship to gene expression status. Leukemia 2008;22:1035-43.
81. Wolff EM, Chihara Y, Pan F, et al. Unique DNA methylation patterns distinguish noninvasive and invasive urothelial cancers and establish an epigenetic field defect in premalignant tissue. Cancer Res 2010;70:8169-78.
82. Easwaran H, Johnstone SE, Van Neste L, et al. A DNA hypermethylation module for the stem/progenitor cell signature of cancer. GenomeRes 2012;22:837-49.
83. Bird A. DNA methylation patterns and epigenetic memory. Genes Dev 2002;16:6-21.
84. Jones PA. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet 2012;13:484-92.
85. Sato S, Yoshida W, Soejima H, et al. Methylation dynamics of IG-DMR and Gtl2-DMR during murine embryonic and placental development. Genomics 2011;98:120-7.
86. Epsztejn-Litman S, Feldman N, Abu-Remaileh M, et al. De novo DNA methylation promoted by G9a prevents reprogramming of embryonically silenced genes. Nat Struct Mol Biol 2008;15:1176-83.
87. Feldman N, Gerson A, Fang J, et al. G9a-mediated irreversible epigenetic inactivation of Oct-3/4 during early embryogenesis. Nat Cell Biol 2006;8:188-94.
88. Mohn F, Weber M, Rebhan M, et al. Lineage-specific polycomb targets and de novo DNA methylation define restriction and potential of neuronal progenitors. Mol Cell 2008; 30:755-66.
89. Mutskov V, Felsenfeld G. Silencing of transgene transcription precedes methylation of promoter DNA and histone H3 lysine 9. EMBOJ 2004;23:138-49.
90. Ruiz S, Diep D, Gore A, et al. Identification of a specific reprogramming-associated epigenetic signature in human induced pluripotent stem cells. Proc Natl Acad Sci USA 2012;109:16196-201.
91. Mikkelsen TS, Hanna J, Zhang X, et al. Dissecting direct reprogramming through integrative genomic analysis. Nature 2008;454:49-55.
92. Baylin SB, Jones PA. A decade of exploring the cancer epigenome-biological and translational implications. Nat Rev Cancer 2011;11:726-34.
93. Kalari S, Pfeifer GP. Identification of driver and passenger DNA methylation in cancer by epigenomic analysis. Adv Genet 2010;70:277-308.
94. Stratton MR, Campbell PJ, Futreal PA. The cancer genome. Nature 2009;458:719-24.
95. Gilbertson RJ, Graham TA. Cancer: resolving the stem-cell debate. Nature 2012;488:462-3.
96. Hosoya K, Yamashita S, Ando T, etal. Adenomatous polyposis coli 1A is likely to be methylated as a passenger in human gastric carcinogenesis. Cancer Lett 2009;285:182-9.
97. Kodzius R, Kojima M, Nishiyori H, et al. CAGE: cap analysis of gene expression. NatMethods 2006;3:211-22.
98. Wu ZQ, Li XY, Hu CY, et al. Canonical Wnt signaling regulates Slug activity and links epithelial-mesenchymal transition with epigenetic Breast Cancer 1, Early Onset (BRCA1) repression. Proc Natl Acad Sci USA 2012;109: 16654-9.
99. Esteller M, Corn PG, Baylin SB, et al. A gene hypermethylation profile of human cancer. Cancer Res 2001;61: 3225-9.
100. Gil J, Peters G. Regulation of the INK4b-ARF-INK4a tumour suppressor locus: all for one or one for all. Nat RevMol Cell Biol 2006;7:667-77.
101. Bracken AP, Kleine-Kohlbrecher D, Dietrich N, et al. The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. Genes Dev 2007;21:525-30.
102. Jacobs JJ, Kieboom K, Marino S, et al. The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 1999;397: 164-8.
103. Bachman KE, Park BH, Rhee I, et al. Histone modifications and silencing prior to DNA methylation of a tumor suppressor gene. Cancer Cell 2003;3:89-95.
104. Hinshelwood RA, Melki JR, Huschtscha LI, et al. Aberrant de novo methylation of the p16INK4A CpG island is initiated post gene silencing in association with chromatin remodelling and mimics nucleosome positioning. HumMol Genet 2009;18:3098-109.
105. Gendrel AV, Apedaile A, Coker H, et al. Smchd1-dependent and -independent pathways determine developmental dynamics of CpG island methylation on the inactive x chromosome. Dev Cell 2012;23:265-79.
106. De Carvalho DD, Sharma S, You JS, et al. DNA methylation screening identifies driver epigenetic events of cancer cell survival. Cancer Cell 2012;21:655-67.
107. Ogino S, Nosho K, Kirkner GJ, et al. CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer. Gut 2009;58: 90-6.
108. Wood LD, Parsons DW, Jones S, et al. The genomic landscapes of human breast and colorectal cancers. Science 2007; 318:1108-13.
109. Ohm JE, McGarvey KM, Yu X, et al. A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat Genet 2007;39:237-42.
110. Schlesinger Y, Straussman R, Keshet I, et al. Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nat Genet 2007;39:232-6.
111. Widschwendter M, Fiegl H, Egle D, et al. Epigenetic stem cell signature in cancer. Nat Genet 2007;39:157-8.
112. Ben-Porath I, Thomson MW, Carey VJ, et al. An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet 2008; 40:499-507.
113. Kim J, Woo AJ, Chu J, et al. A Myc network accounts for similarities between embryonic stem and cancer cell transcription programs. Cell 2010;143:313-24.
114. Bracken AP, Dietrich N, Pasini D, et al. Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. GenesDev 2006;20:1123-36.
115. Helman E, Naxerova K, Kohane IS. DNA hypermethylation in lung cancer is targeted at differentiation-associated genes. Oncogene 2012;31:1181-8.
116. Sasaki M, Knobbe CB, Munger JC, et al. IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature 2012;488:656-9.
117. Sasaki M, Knobbe CB, Itsumi M, et al. D-2-hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function. Genes Dev 2012;26:2038-49.
118. Xu W, Yang H, Liu Y, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alphaketoglutarate- dependent dioxygenases. Cancer Cell 2011; 19:17-30.
119. Nguyen DX, Bos PD, Massague J. Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer 2009;9:274-84.
120. Lord CJ, Ashworth A. The DNA damage response and cancer therapy. Nature 2012;481:287-94.
121. McDermott U, Downing JR, Stratton MR. Genomics and the continuum of cancer care. N Engl J Med 2011;364: 340-50.
122. Adams PD. Remodeling of chromatin structure in senescent cells and its potential impact on tumor suppression and aging. Gene 2007;397:84-93.
123. Feinberg AP, Ohlsson R, Henikoff S. The epigenetic progenitor origin of human cancer. Nat Rev Genet 2006;7: 21-33.
124. Issa JP, Vertino PM, Wu J, et al. Increased cytosine DNA-methyltransferase activity during colon cancer progression. JNatl Cancer Inst 1993;85:1235-40.
125. el-Deiry WS, Nelkin BD, Celano P, et al. High expression of the DNA methyltransferase gene characterizes human neoplastic cells and progression stages of colon cancer. Proc Natl Acad Sci USA 1991;88:3470-4.
126. Eads CA, Danenberg KD, Kawakami K, et al. CpG island hypermethylation in human colorectal tumors is not associated with DNA methyltransferase overexpression. Cancer Res 1999;59:2302-6.
127. Robertson KD, Keyomarsi K, Gonzales FA, et al. Differential mRNA expression of the human DNA methyltransferases (DNMTs) 1, 3a and 3b during the G(0)/G(1) to S phase transition in normal and tumor cells. Nucleic Acids Res 2000;28:2108-13.
128. Ibrahim AE, Arends MJ, Silva AL, et al. Sequential DNA methylation changes are associated with DNMT3B overexpression in colorectal neoplastic progression. Gut 2011; 60:499-508.
129. Laird PW, Jackson-Grusby L, Fazeli A, et al. Suppression of intestinal neoplasia by DNA hypomethylation. Cell 1995; 81:197-205.
130. Lin H, Yamada Y, Nguyen S, etal. Suppression of intestinal neoplasia by deletion of Dnmt3b. Mol Cell Biol 2006;26: 2976-83.
131. Linhart HG, Lin H, Yamada Y, et al. Dnmt3b promotes tumorigenesis in vivo by gene-specific de novo methylation and transcriptional silencing. Genes Dev 2007;21: 3110-22.
132. Steine EJ, Ehrich M, Bell GW, et al. Genes methylated by DNA methyltransferase 3b are similar in mouse intestine and human colon cancer. J Clin Invest 2011;121: 1748-52.
133. Ley TJ, Ding L, Walter MJ, et al. DNMT3A mutations in acute myeloid leukemia. N Engl JMed 2010;363: 2424-33.
134. Walter MJ, Ding L, Shen D, et al. Recurrent DNMT3A mutations in patients with myelodysplastic syndromes. Leukemia 2011;25:1153-8.
135. Yan XJ, Xu J, Gu ZH, et al. Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nat Genet 2011; 43:309-15.
136. Ribeiro AF, Pratcorona M, Erpelinck-Verschueren C, et al. Mutant DNMT3A: a marker of poor prognosis in acute myeloid leukemia. Blood 2012;119:5824-31.
137. Shah MY, Vasanthakumar A, Barnes NY, et al. DNMT3B7, a truncated DNMT3B isoform expressed in human tumors, disrupts embryonic development and accelerates lymphomagenesis. Cancer Res 2010;70:5840-50.
138. Goll MG, Bestor TH. Eukaryotic cytosine methyltransferases. Annu Rev Biochem 2005;74:481-514.
139. Van Emburgh BO, Robertson KD. Modulation of Dnmt3b function in vitro by interactions with Dnmt3L, Dnmt3a and Dnmt3b splice variants. Nucleic Acids Res 2011;39:4984-5002.
140. Prokhortchouk A, Sansom O, Selfridge J, et al. Kaiso-deficient mice show resistance to intestinal cancer. Mol Cell Biol 2006;26:199-208.
141. Sansom OJ, Berger J, Bishop SM, etal. Deficiency of Mbd2 suppresses intestinal tumorigenesis. Nat Genet 2003;34: 145-7.
142. Vire E, Brenner C, Deplus R, et al. The Polycomb group protein EZH2 directly controls DNA methylation. Nature 2006;439:871-4.
143. Denis H, Ndlovu MN, Fuks F. Regulation of mammalian DNA methyltransferases: a route to new mechanisms. EMBORep 2011;12:647-56.
144. Rush M, Appanah R, Lee S, et al. Targeting of EZH2 to a defined genomic site is sufficient for recruitment of Dnmt3a but not de novo DNA methylation. Epigenetics 2009;4:404-14.
145. Fouse SD, Shen Y, Pellegrini M, et al. Promoter CpG methylation contributes to ES cell gene regulation in parallel with Oct4/Nanog, PcG complex, and histone H3 K4/K27 trimethylation. Cell Stem Cell 2008;2:160-9.
146. Kondo Y, Shen L, Cheng AS, etal. Gene silencing in cancer by histone H3 lysine 27 trimethylation independent of promoter DNA methylation. Nat Genet 2008;40:741-50.
147. Statham AL, Robinson MD, Song JZ, et al. Bisulfite sequencing of chromatin immunoprecipitated DNA (BisChIP-seq) directly informs methylation status of histone-modified DNA. Genome Res 2012;22:1120-7.
148. Brinkman AB, Gu H, Bartels SJ, et al. Sequential ChIP-bisulfite sequencing enables direct genome-scale investigation of chromatin and DNA methylation cross-talk. GenomeRes 2012;22:1128-38.
149. Lynch MD, Smith AJ, De Gobbi M, et al. An interspecies analysis reveals a key role for unmethylated CpG dinucleotides in vertebrate Polycomb complex recruitment. EMBO J 2012;31:317-29.
150. Gal-Yam EN, Egger G, Iniguez L, etal. Frequent switching of Polycomb repressive marks and DNA hypermethylation in the PC3 prostate cancer cell line. ProcNatlAcad SciUSA 2008;105:12979-84.
151. Meissner A, Mikkelsen TS, Gu H, et al. Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 2008;454:766-70.
152. Thomson JP, Skene PJ, Selfridge J, et al. CpG islands influence chromatin structure via the CpG-binding protein Cfp1. Nature 2010;464:1082-6.
153. Ooi SK, Qiu C, Bernstein E, et al. DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature 2007;448:714-7.
154. Clouaire T, Webb S, Skene P, et al. Cfp1 integrates both CpG content and gene activity for accurate H3K4me3 deposition in embryonic stem cells. Genes Dev 2012;26: 1714-28.
155. Zilberman D, Coleman-Derr D, Ballinger T, et al. Histone H2A.Z and DNA methylation are mutually antagonistic chromatin marks. Nature 2008;456:125-9.
156. Zemach A, McDaniel IE, Silva P, et al. Genome-wide evolutionary analysis of eukaryotic DNA methylation. Science 2010;328:916-9.
157. Conerly ML, Teves SS, Diolaiti D, etal. Changes in H2A.Z occupancy and DNA methylation during B-cell lymphomagenesis. GenomeRes 2010;20:1383-90.
158. Franchini DM, Schmitz KM, Petersen-Mahrt SK. 5-methylcytosine DNA demethylation: more than losing a methyl group. Annu RevGenet 2012;46:419-41.
159. Tahiliani M, Koh KP, Shen Y, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 2009; 324:930-5.
160. Williams K, Christensen J, Pedersen MT, et al. TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity. Nature 2011;473:343-8.
161. Wu H, D'Alessio AC, Ito S, et al. Dual functions of Tet1 in transcriptional regulation in mouse embryonic stem cells. Nature 2011;473:389-93.
162. Williams K, Christensen J, Helin K. DNA methylation: TET proteins-guardians of CpG islands? EMBO Rep 2012;13:28-35.
163. Abdel-Wahab O, Mullally A, Hedvat C, et al. Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood 2009;114:144-147.
164. Gertz J, Varley KE, Reddy TE, et al. Analysis of DNA methylation in a three-generation family reveals widespread genetic influence on epigenetic regulation. PLoS Genet 2011;7:e1002228.
165. Lienert F, Wirbelauer C, Som I, et al. Identification of genetic elements that autonomously determine DNA methylation states. Nat Genet 2011;43:1091-7.
166. Thurman RE, Rynes E, Humbert R, et al. The accessible chromatin landscape of the human genome. Nature 2012; 489:75-82.
167. Hervouet E, Vallette FM, Cartron PF. Dnmt3/transcription factor interactions as crucial players in targeted DNA methylation. Epigenetics 2009;4:487-99.
168. Di Croce L, Raker VA, Corsaro M, et al. Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science 2002; 295:1079-82.
169. Feltus FA, Lee EK, Costello JF, et al. Predicting aberrant CpG island methylation. Proc Natl Acad Sci USA 2003;100: 12253-8.
170. Gebhard C, Benner C, Ehrich M, et al. General transcription factor binding at CpG islands in normal cells correlates with resistance to de novo DNA methylation in cancer cells. Cancer Res 2010;70:1398-407.
171. Takeshima H, Yamashita S, Shimazu T, et al. The presence of RNA polymerase II, active or stalled, predicts epigenetic fate of promoter CpG islands. Genome Res 2009;19: 1974-82.
172. Boumber YA, Kondo Y, Chen X, et al. An Sp1/Sp3 binding polymorphism confers methylation protection. PLoS Genet 2008;4:e1000162.
173. Brookes E, de Santiago I, Hebenstreit D, et al. Polycomb associates genome-wide with a specific RNA polymerase II variant, and regulates metabolic genes in ESCs. Cell Stem Cell 2012;10:157-70.
174. Enderle D, Beisel C, Stadler MB, et al. Polycomb preferentially targets stalled promoters of coding and noncoding transcripts. Genome Res 2011;21:216-26.
175. Holm K, Hegardt C, Staaf J, etal. Molecular subtypes of breast cancer are associated with characteristic DNA methylation patterns. BreastCancerRes 2010;12:R36.
176. Bernstein BE, Mikkelsen TS, Xie X, et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 2006;125:315-26.
177. De Gobbi M, Garrick D, Lynch M, et al. Generation of bivalent chromatin domains during cell fate decisions. Epigenetics Chromatin 2011;4:9.
178. Estecio MR, Gallegos J, Vallot C, et al. Genome architecture marked by retrotransposons modulates predisposition to DNA methylation in cancer. Genome Res 2010;20: 1369-82.
179. Ohm JE, Baylin SB. Stem cell chromatin patterns: an instructive mechanism for DNA hypermethylation?. Cell Cycle 2007;6:1040-3.
180. Landan G, Cohen NM, Mukamel Z, etal. Epigenetic polymorphism and the stochastic formation of differentially methylated regions in normal and cancerous tissues. Nat Genet 2012;44:1207-14.
181. Rakyan VK, Down TA, Balding DJ, et al. Epigenomewide association studies for common human diseases. Nat Rev Genet 2011;12:529-41.
182. Heyn H, Esteller M. DNA methylation profiling in the clinic: applications and challenges. Nat Rev Genet 2012;13: 679-92.
183. Vanharanta S, Shu W, Brenet F, et al. Epigenetic expansion of VHL-HIF signal output drives multiorgan metastasis in renal cancer. NatMed 2013;19:50-6.