Intragenic DNA methylation in transcriptional regulation, normal differentiation and cancer

Biochimica et Biophysica Acta - Gene Regulatory Mechanisms

Volumn 1829, Issue 11, 2013, Pages 1161-1174

  Kulis, Marta ^a   Queirós, Ana C ^a   Beekman, Renée ^a   Martín Subero, José I ^a  

^a UNIVERSITY OF BARCELONA   (Spain)

Author keywords

Cancer; Cell differentiation; DNA methylation; Enhancer; Gene body; Transcription regulation

Indexed keywords

DNA; LONG UNTRANSLATED RNA;

ACUTE GRANULOCYTIC LEUKEMIA; CARCINOGENESIS; CELL DIFFERENTIATION; CELL MATURATION; CHROMATIN CONDENSATION; CHRONIC LYMPHATIC LEUKEMIA; DNA BINDING; DNA METHYLATION; ESOPHAGEAL ADENOCARCINOMA; GENE ACTIVATION; GENE CONTROL; GENE EXPRESSION; GENETIC TRANSCRIPTION; HUMAN; LUNG ADENOCARCINOMA; MALIGNANT TRANSFORMATION; NEOPLASM; NONHUMAN; PRIORITY JOURNAL; PROMOTER REGION; REVIEW; RNA PROCESSING; RNA SEQUENCE; TESTIS CANCER; TRANSCRIPTION REGULATION; TRANSPOSON;

CANCER; CELL DIFFERENTIATION; DNA METHYLATION; ENHANCER; GENE BODY; TRANSCRIPTION REGULATION;

CELL DIFFERENTIATION; DNA METHYLATION; DNA TRANSPOSABLE ELEMENTS; ENHANCER ELEMENTS, GENETIC; GENE EXPRESSION REGULATION; HUMANS; NEOPLASMS; PROMOTER REGIONS, GENETIC; RNA PROCESSING, POST-TRANSCRIPTIONAL; TRANSCRIPTION, GENETIC;

EID: 84884759753     PISSN: 18749399     EISSN: 18764320     Source Type: Journal    
DOI: 10.1016/j.bbagrm.2013.08.001     Document Type: Review

References (175)

1. Holliday R., Pugh J.E. DNA modification mechanisms and gene activity during development. Science 1975, 187:226-232.
2. Riggs A.D. X inactivation, differentiation, and DNA methylation. Cytogenet. Cell Genet. 1975, 14:9-25.
3. Jones P.A., Taylor S.M. Cellular differentiation, cytidine analogs and DNA methylation. Cell 1980, 20:85-93.
4. Razin A., Riggs A.D. DNA methylation and gene function. Science 1980, 210:604-610.
5. McGhee J.D., Ginder G.D. Specific DNA methylation sites in the vicinity of the chicken beta-globin genes. Nature 1979, 280:419-420.
6. Stein R., Gruenbaum Y., Pollack Y., Razin A., Cedar H. Clonal inheritance of the pattern of DNA methylation in mouse cells. Proc. Natl. Acad. Sci. U. S. A. 1982, 79:61-65.
7. Mohandas T., Sparkes R.S., Shapiro L.J. Reactivation of an inactive human X chromosome: evidence for X inactivation by DNA methylation. Science 1981, 211:393-396.
8. Illingworth R.S., Bird A.P. CpG islands-'a rough guide'. FEBS Lett. 2009, 583:1713-1720.
9. Saxonov S., Berg P., Brutlag D.L. A genome-wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promoters. Proc. Natl. Acad. Sci. U. S. A. 2006, 103:1412-1417.
10. Bird A., Taggart M., Frommer M., Miller O.J., Macleod D. A fraction of the mouse genome that is derived from islands of nonmethylated, CpG-rich DNA. Cell 1985, 40:91-99.
11. Tykocinski M.L., Max E.E. CG dinucleotide clusters in MHC genes and in 5' demethylated genes. Nucleic Acids Res. 1984, 12:4385-4396.
12. Antequera F., Boyes J., Bird A. High levels of de novo methylation and altered chromatin structure at CpG islands in cell lines. Cell 1990, 62:503-514.
13. Hansen R.S., Gartler S.M. 5-Azacytidine-induced reactivation of the human X chromosome-linked PGK1 gene is associated with a large region of cytosine demethylation in the 5' CpG island. Proc. Natl. Acad. Sci. U. S. A. 1990, 87:4174-4178.
14. Merlo A., Herman J.G., Mao L., Lee D.J., Gabrielson E., Burger P.C., Baylin S.B., Sidransky D. 5' CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat. Med. 1995, 1:686-692.
15. Sakai T., Toguchida J., Ohtani N., Yandell D.W., Rapaport J.M., Dryja T.P. Allele-specific hypermethylation of the retinoblastoma tumor-suppressor gene. Am. J. Hum. Genet. 1991, 48:880-888.
16. Yoshiura K., Kanai Y., Ochiai A., Shimoyama Y., Sugimura T., Hirohashi S. Silencing of the E-cadherin invasion-suppressor gene by CpG methylation in human carcinomas. Proc. Natl. Acad. Sci. U. S. A. 1995, 92:7416-7419.
17. Esteller M. Epigenetics in cancer. N. Engl. J. Med. 2008, 358:1148-1159.
18. Jones P.A., Baylin S.B. The fundamental role of epigenetic events in cancer. Nat. Rev. 2002, 3:415-428.
19. Feinberg A.P., Vogelstein B. Hypomethylation of ras oncogenes in primary human cancers. Biochem. Biophys. Res. Commun. 1983, 111:47-54.
20. Feinberg A.P., Vogelstein B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 1983, 301:89-92.
21. Gama-Sosa M.A., Slagel V.A., Trewyn R.W., Oxenhandler R., Kuo K.C., Gehrke C.W., Ehrlich M. The 5-methylcytosine content of DNA from human tumors. Nucleic Acids Res. 1983, 11:6883-6894.
22. Ehrlich M. DNA methylation in cancer: too much, but also too little. Oncogene 2002, 21:5400-5413.
23. Waalwijk C., Flavell R.A. DNA methylation at a CCGG sequence in the large intron of the rabbit beta-globin gene: tissue-specific variations. Nucleic Acids Res. 1978, 5:4631-4634.
24. Wang R.Y., Gehrke C.W., Ehrlich M. Comparison of bisulfite modification of 5-methyldeoxycytidine and deoxycytidine residues. Nucleic Acids Res. 1980, 8:4777-4790.
25. Cross S.H., Charlton J.A., Nan X., Bird A.P. Purification of CpG islands using a methylated DNA binding column. Nat. Genet. 1994, 6:236-244.
26. Laird P.W. Principles and challenges of genomewide DNA methylation analysis. Nat. Rev. 2010, 11:191-203.
27. Frommer M., McDonald L.E., Millar D.S., Collis C.M., Watt F., Grigg G.W., Molloy P.L., Paul C.L. A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands. Proc. Natl. Acad. Sci. U. S. A. 1992, 89:1827-1831.
28. Herman J.G., Graff J.R., Myohanen S., Nelkin B.D., Baylin S.B. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc. Natl. Acad. Sci. U. S. A. 1996, 93:9821-9826.
29. Khulan B., Thompson R.F., Ye K., Fazzari M.J., Suzuki M., Stasiek E., Figueroa M.E., Glass J.L., Chen Q., Montagna C., Hatchwell E., Selzer R.R., Richmond T.A., Green R.D., Melnick A., Greally J.M. Comparative isoschizomer profiling of cytosine methylation: the HELP assay. Genome Res. 2006, 16:1046-1055.
30. Weber M., Hellmann I., Stadler M.B., Ramos L., Paabo S., Rebhan M., Schubeler D. Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nat. Genet. 2007, 39:457-466.
31. Bibikova M., Barnes B., Tsan C., Ho V., Klotzle B., Le J.M., Delano D., Zhang L., Schroth G.P., Gunderson K.L., Fan J.B., Shen R. High density DNA methylation array with single CpG site resolution. Genomics 2011, 98:288-295.
32. Irizarry R.A., Ladd-Acosta C., Carvalho B., Wu H., Brandenburg S.A., Jeddeloh J.A., Wen B., Feinberg A.P. Comprehensive high-throughput arrays for relative methylation (CHARM). Genome Res. 2008, 18:780-790.
33. Illingworth R.S., Gruenewald-Schneider U., Webb S., Kerr A.R., James K.D., Turner D.J., Smith C., Harrison D.J., Andrews R., Bird A.P. Orphan CpG islands identify numerous conserved promoters in the mammalian genome. PLoS Genet. 2010, 6:e1001134.
34. Lister R., Pelizzola M., Dowen R.H., Hawkins R.D., Hon G., Tonti-Filippini J., Nery J.R., Lee L., Ye Z., Ngo Q.M., Edsall L., Antosiewicz-Bourget J., Stewart R., Ruotti V., Millar A.H., Thomson J.A., Ren B., Ecker J.R. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 2009, 462:315-322.
35. Maunakea A.K., Nagarajan R.P., Bilenky M., Ballinger T.J., D'Souza C., Fouse S.D., Johnson B.E., Hong C., Nielsen C., Zhao Y., Turecki G., Delaney A., Varhol R., Thiessen N., Shchors K., Heine V.M., Rowitch D.H., Xing X., Fiore C., Schillebeeckx M., Jones S.J., Haussler D., Marra M.A., Hirst M., Wang T., Costello J.F. Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature 2010, 466:253-257.
36. Meissner A., Gnirke A., Bell G.W., Ramsahoye B., Lander E.S., Jaenisch R. Reduced representation bisulfite sequencing for comparative high-resolution DNA methylation analysis. Nucleic Acids Res. 2005, 33:5868-5877.
37. Jones P.A. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat. Rev. 2012, 13:484-492.
38. Jones P.A., Taylor S.M., Mohandas T., Shapiro L.J. Cell cycle-specific reactivation of an inactive X-chromosome locus by 5-azadeoxycytidine. Proc. Natl. Acad. Sci. U. S. A. 1982, 79:1215-1219.
39. Venolia L., Gartler S.M., Wassman E.R., Yen P., Mohandas T., Shapiro L.J. Transformation with DNA from 5-azacytidine-reactivated X chromosomes. Proc. Natl. Acad. Sci. U. S. A. 1982, 79:2352-2354.
40. Rhee I., Bachman K.E., Park B.H., Jair K.W., Yen R.W., Schuebel K.E., Cui H., Feinberg A.P., Lengauer C., Kinzler K.W., Baylin S.B., Vogelstein B. DNMT1 and DNMT3b cooperate to silence genes in human cancer cells. Nature 2002, 416:552-556.
41. Robert M.F., Morin S., Beaulieu N., Gauthier F., Chute I.C., Barsalou A., MacLeod A.R. DNMT1 is required to maintain CpG methylation and aberrant gene silencing in human cancer cells. Nat. Genet. 2003, 33:61-65.
42. Ballestar E., Wolffe A.P. Methyl-CpG-binding proteins. Targeting specific gene repression. Eur. J. Biochem. 2001, 268:1-6.
43. Bird A. DNA methylation patterns and epigenetic memory. Genes Dev. 2002, 16:6-21.
44. Dong Z., Wang X., Evers B.M. Site-specific DNA methylation contributes to neurotensin/neuromedin N expression in colon cancers. Am. J. Physiol. Gastrointest. Liver Physiol. 2000, 279:G1139-G1147.
45. Hark A.T., Schoenherr C.J., Katz D.J., Ingram R.S., Levorse J.M., Tilghman S.M. CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus. Nature 2000, 405:486-489.
46. Mancini D.N., Singh S.M., Archer T.K., Rodenhiser D.I. Site-specific DNA methylation in the neurofibromatosis (NF1) promoter interferes with binding of CREB and SP1 transcription factors. Oncogene 1999, 18:4108-4119.
47. Bergman Y., Cedar H. DNA methylation dynamics in health and disease. Nat. Struct. Mol. Biol. 2013, 20:274-281.
48. Cao R., Wang L., Wang H., Xia L., Erdjument-Bromage H., Tempst P., Jones R.S., Zhang Y. Role of histone H3 lysine 27 methylation in polycomb-group silencing. Science 2002, 298:1039-1043.
49. Lock L.F., Takagi N., Martin G.R. Methylation of the Hprt gene on the inactive X occurs after chromosome inactivation. Cell 1987, 48:39-46.
50. Gal-Yam E.N., Egger G., Iniguez L., Holster H., Einarsson S., Zhang X., Lin J.C., Liang G., Jones P.A., Tanay A. Frequent switching of polycomb repressive marks and DNA hypermethylation in the PC3 prostate cancer cell line. Proc. Natl. Acad. Sci. U. S. A. 2008, 105:12979-12984.
51. Keshet I., Schlesinger Y., Farkash S., Rand E., Hecht M., Segal E., Pikarski E., Young R.A., Niveleau A., Cedar H., Simon I. Evidence for an instructive mechanism of de novo methylation in cancer cells. Nat. Genet. 2006, 38:149-153.
52. Pannell D., Osborne C.S., Yao S., Sukonnik T., Pasceri P., Karaiskakis A., Okano M., Li E., Lipshitz H.D., Ellis J. Retrovirus vector silencing is de novo methylase independent and marked by a repressive histone code. EMBO J. 2000, 19:5884-5894.
53. 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 2011, 6:e18844.
54. Ball M.P., Li J.B., Gao Y., Lee J.H., LeProust E.M., Park I.H., Xie B., Daley G.Q., Church G.M. Targeted and genome-scale strategies reveal gene-body methylation signatures in human cells. Nat. Biotechnol. 2009, 27:361-368.
55. Hon G.C., Hawkins R.D., Caballero O.L., Lo C., Lister R., Pelizzola M., Valsesia A., Ye Z., Kuan S., Edsall L.E., Camargo A.A., Stevenson B.J., Ecker J.R., Bafna V., Strausberg R.L., Simpson A.J., Ren B. Global DNA hypomethylation coupled to repressive chromatin domain formation and gene silencing in breast cancer. Genome Res. 2012, 22:246-258.
56. Kulis M., Heath S., Bibikova M., Queiros A.C., Navarro A., Clot G., Martinez-Trillos A., Castellano G., Brun-Heath I., Pinyol M., Barberan-Soler S., Papasaikas P., Jares P., Bea S., Rico D., Ecker S., Rubio M., Royo R., Ho V., Klotzle B., Hernandez L., Conde L., Lopez-Guerra M., Colomer D., Villamor N., Aymerich M., Rozman M., Bayes M., Gut M., Gelpi J.L., Orozco M., Fan J.B., Quesada V., Puente X.S., Pisano D.G., Valencia A., Lopez-Guillermo A., Gut I., Lopez-Otin C., Campo E., Martin-Subero J.I. Epigenomic analysis detects widespread gene-body DNA hypomethylation in chronic lymphocytic leukemia. Nat. Genet. 2012, 44:1236-1242.
57. Rakyan V.K., Down T.A., Thorne N.P., Flicek P., Kulesha E., Graf S., Tomazou E.M., Backdahl L., Johnson N., Herberth M., Howe K.L., Jackson D.K., Miretti M.M., Fiegler H., Marioni J.C., Birney E., Hubbard T.J., Carter N.P., Tavare S., Beck S. An integrated resource for genome-wide identification and analysis of human tissue-specific differentially methylated regions (tDMRs). Genome Res. 2008, 18:1518-1529.
58. Rauch T.A., Wu X., Zhong X., Riggs A.D., Pfeifer G.P. A human B cell methylome at 100-base pair resolution. Proc. Natl. Acad. Sci. U. S. A. 2009, 106:671-678.
59. Hellman A., Chess A. Gene body-specific methylation on the active X chromosome. Science 2007, 315:1141-1143.
60. Aran D., Toperoff G., Rosenberg M., Hellman A. Replication timing-related and gene body-specific methylation of active human genes. Hum. Mol. Genet. 2010, 20:670-680.
61. Suzuki M., Oda M., Ramos M.P., Pascual M., Lau K., Stasiek E., Agyiri F., Thompson R.F., Glass J.L., Jing Q., Sandstrom R., Fazzari M.J., Hansen R.S., Stamatoyannopoulos J.A., McLellan A.S., Greally J.M. Late-replicating heterochromatin is characterized by decreased cytosine methylation in the human genome. Genome Res. 2011, 21:1833-1840.
62. Zhang J., Xu F., Hashimshony T., Keshet I., Cedar H. Establishment of transcriptional competence in early and late S phase. Nature 2002, 420:198-202.
63. Berman B.P., Weisenberger D.J., Aman J.F., Hinoue T., Ramjan Z., Liu Y., Noushmehr H., Lange C.P., van Dijk C.M., Tollenaar R.A., Van Den Berg D., Laird P.W. Regions of focal DNA hypermethylation and long-range hypomethylation in colorectal cancer coincide with nuclear lamina-associated domains. Nat. Genet. 2012, 44:40-46.
64. Robertson K.D., Keyomarsi K., Gonzales F.A., Velicescu M., Jones P.A. 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, 28:2108-2113.
65. Jjingo D., Conley A.B., Yi S.V., Lunyak V.V., Jordan I.K. On the presence and role of human gene-body DNA methylation. Oncotarget 2012, 3:462-474.
66. Varley K.E., Gertz J., Bowling K.M., Parker S.L., Reddy T.E., Pauli-Behn F., Cross M.K., Williams B.A., Stamatoyannopoulos J.A., Crawford G.E., Absher D.M., Wold B.J., Myers R.M. Dynamic DNA methylation across diverse human cell lines and tissues. Genome Res. 2013, 23:555-567.
67. Archey W.B., Sweet M.P., Alig G.C., Arrick B.A. Methylation of CpGs as a determinant of transcriptional activation at alternative promoters for transforming growth factor-beta3. Cancer Res. 1999, 59:2292-2296.
68. Shmelkov S.V., Jun L., St Clair R., McGarrigle D., Derderian C.A., Usenko J.K., Costa C., Zhang F., Guo X., Rafii S. Alternative promoters regulate transcription of the gene that encodes stem cell surface protein AC133. Blood 2004, 103:2055-2061.
69. Kimura K., Wakamatsu A., Suzuki Y., Ota T., Nishikawa T., Yamashita R., Yamamoto J., Sekine M., Tsuritani K., Wakaguri H., Ishii S., Sugiyama T., Saito K., Isono Y., Irie R., Kushida N., Yoneyama T., Otsuka R., Kanda K., Yokoi T., Kondo H., Wagatsuma M., Murakawa K., Ishida S., Ishibashi T., Takahashi-Fujii A., Tanase T., Nagai K., Kikuchi H., Nakai K., Isogai T., Sugano S. Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome Res. 2006, 16:55-65.
70. Cheong J., Yamada Y., Yamashita R., Irie T., Kanai A., Wakaguri H., Nakai K., Ito T., Saito I., Sugano S., Suzuki Y. Diverse DNA methylation statuses at alternative promoters of human genes in various tissues. DNA Res. 2006, 13:155-167.
71. Kanber D., Berulava T., Ammerpohl O., Mitter D., Richter J., Siebert R., Horsthemke B., Lohmann D., Buiting K. The human retinoblastoma gene is imprinted. PLoS Genet. 2009, 5:e1000790.
72. Hinske L.C., Galante P.A., Kuo W.P., Ohno-Machado L. A potential role for intragenic miRNAs on their hosts' interactome. BMC Genomics 2010, 11:533.
73. Li S.C., Tang P., Lin W.C. Intronic microRNA: discovery and biological implications. DNA Cell Biol. 2007, 26:195-207.
74. Baer C., Claus R., Frenzel L.P., Zucknick M., Park Y.J., Gu L., Weichenhan D., Fischer M., Pallasch C.P., Herpel E., Rehli M., Byrd J.C., Wendtner C.M., Plass C. Extensive promoter DNA hypermethylation and hypomethylation is associated with aberrant microRNA expression in chronic lymphocytic leukemia. Cancer Res. 2012, 72:3775-3785.
75. Deng S., Calin G.A., Croce C.M., Coukos G., Zhang L. Mechanisms of microRNA deregulation in human cancer. Cell Cycle 2008, 7:2643-2646.
76. Iorio M.V., Piovan C., Croce C.M. Interplay between microRNAs and the epigenetic machinery: an intricate network. Biochim. Biophys. Acta 2010, 1799:694-701.
77. Lujambio A., Ropero S., Ballestar E., Fraga M.F., Cerrato C., Setien F., Casado S., Suarez-Gauthier A., Sanchez-Cespedes M., Git A., Spiteri I., Das P.P., Caldas C., Miska E., Esteller M. Genetic unmasking of an epigenetically silenced microRNA in human cancer cells. Cancer Res. 2007, 67:1424-1429.
78. Saito Y., Liang G., Egger G., Friedman J.M., Chuang J.C., Coetzee G.A., Jones P.A. Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatin-modifying drugs in human cancer cells. Cancer Cell 2006, 9:435-443.
79. Brueckner B., Stresemann C., Kuner R., Mund C., Musch T., Meister M., Sultmann H., Lyko F. The human let-7a-3 locus contains an epigenetically regulated microRNA gene with oncogenic function. Cancer Res. 2007, 67:1419-1423.
80. Cheung H.H., Davis A.J., Lee T.L., Pang A.L., Nagrani S., Rennert O.M., Chan W.Y. Methylation of an intronic region regulates miR-199a in testicular tumor malignancy. Oncogene 2011, 30:3404-3415.
81. Mercer T.R., Dinger M.E., Mattick J.S. Long non-coding RNAs: insights into functions. Nat. Rev. 2009, 10:155-159.
82. Ponting C.P., Oliver P.L., Reik W. Evolution and functions of long noncoding RNAs. Cell 2009, 136:629-641.
83. Lyle R., Watanabe D., te Vruchte D., Lerchner W., Smrzka O.W., Wutz A., Schageman J., Hahner L., Davies C., Barlow D.P. The imprinted antisense RNA at the Igf2r locus overlaps but does not imprint Mas1. Nat. Genet. 2000, 25:19-21.
84. Stoger R., Kubicka P., Liu C.G., Kafri T., Razin A., Cedar H., Barlow D.P. Maternal-specific methylation of the imprinted mouse Igf2r locus identifies the expressed locus as carrying the imprinting signal. Cell 1993, 73:61-71.
85. Wu W., Bhagat T.D., Yang X., Song J.H., Cheng Y., Agarwal R., Abraham J.M., Ibrahim S., Bartenstein M., Hussain Z., Suzuki M., Yu Y., Chen W., Eng C., Greally J., Verma A., Meltzer S.J. Hypomethylation of noncoding DNA regions and overexpression of the long noncoding RNA, AFAP1-AS1, in Barrett's esophagus and esophageal adenocarcinoma. Gastroenterology 2013, 144:956-966. (e954).
86. Hoffmann M.J., Schulz W.A. Causes and consequences of DNA hypomethylation in human cancer. Biochem. Cell Biol. 2005, 83:296-321.
87. Aporntewan C., Phokaew C., Piriyapongsa J., Ngamphiw C., Ittiwut C., Tongsima S., Mutirangura A. Hypomethylation of intragenic LINE-1 represses transcription in cancer cells through AGO2. PLoS One 2011, 6:e17934.
88. Saied M.H., Marzec J., Khalid S., Smith P., Down T.A., Rakyan V.K., Molloy G., Raghavan M., Debernardi S., Young B.D. Genome wide analysis of acute myeloid leukemia reveal leukemia specific methylome and subtype specific hypomethylation of repeats. PLoS One 2012, 7:e33213.
89. Lorincz M.C., Dickerson D.R., Schmitt M., Groudine M. Intragenic DNA methylation alters chromatin structure and elongation efficiency in mammalian cells. Nat. Struct. Mol. Biol. 2004, 11:1068-1075.
90. Brown S.J., Stoilov P., Xing Y. Chromatin and epigenetic regulation of pre-mRNA processing. Hum. Mol. Genet. 2012, 21:R90-R96.
91. Chasin L.A. Searching for splicing motifs. Adv. Exp. Med. Biol. 2007, 623:85-106.
92. Luco R.F., Allo M., Schor I.E., Kornblihtt A.R., Misteli T. Epigenetics in alternative pre-mRNA splicing. Cell 2011, 144:16-26.
93. Luco R.F., Pan Q., Tominaga K., Blencowe B.J., Pereira-Smith O.M., Misteli T. Regulation of alternative splicing by histone modifications. Science 2010, 327:996-1000.
94. Schwartz S., Meshorer E., Ast G. Chromatin organization marks exon-intron structure. Nat. Struct. Mol. Biol. 2009, 16:990-995.
95. Tilgner H., Nikolaou C., Althammer S., Sammeth M., Beato M., Valcarcel J., Guigo R. Nucleosome positioning as a determinant of exon recognition. Nat. Struct. Mol. Biol. 2009, 16:996-1001.
96. Andersson R., Enroth S., Rada-Iglesias A., Wadelius C., Komorowski J. Nucleosomes are well positioned in exons and carry characteristic histone modifications. Genome Res. 2009, 19:1732-1741.
97. Chen W., Luo L., Zhang L. The organization of nucleosomes around splice sites. Nucleic Acids Res. 2010, 38:2788-2798.
98. Chodavarapu R.K., Feng S., Bernatavichute Y.V., Chen P.Y., Stroud H., Yu Y., Hetzel J.A., Kuo F., Kim J., Cokus S.J., Casero D., Bernal M., Huijser P., Clark A.T., Kramer U., Merchant S.S., Zhang X., Jacobsen S.E., Pellegrini M. Relationship between nucleosome positioning and DNA methylation. Nature 2010, 466:388-392.
99. Hodges E., Smith A.D., Kendall J., Xuan Z., Ravi K., Rooks M., Zhang M.Q., Ye K., Bhattacharjee A., Brizuela L., McCombie W.R., Wigler M., Hannon G.J., Hicks J.B. High definition profiling of mammalian DNA methylation by array capture and single molecule bisulfite sequencing. Genome Res. 2009, 19:1593-1605.
100. Kolasinska-Zwierz P., Down T., Latorre I., Liu T., Liu X.S., Ahringer J. Differential chromatin marking of introns and expressed exons by H3K36me3. Nat. Genet. 2009, 41:376-381.
101. Malousi A., Maglaveras N., Kouidou S. Intronic CpG content and alternative splicing in human genes containing a single cassette exon. Epigenetics 2008, 3:69-73.
102. Anastasiadou C., Malousi A., Maglaveras N., Kouidou S. Human epigenome data reveal increased CpG methylation in alternatively spliced sites and putative exonic splicing enhancers. DNA Cell Biol. 2011, 30:267-275.
103. Shukla S., Kavak E., Gregory M., Imashimizu M., Shutinoski B., Kashlev M., Oberdoerffer P., Sandberg R., Oberdoerffer S. CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing. Nature 2011, 479:74-79.
104. Quesada V., Conde L., Villamor N., Ordonez G.R., Jares P., Bassaganyas L., Ramsay A.J., Bea S., Pinyol M., Martinez-Trillos A., Lopez-Guerra M., Colomer D., Navarro A., Baumann T., Aymerich M., Rozman M., Delgado J., Gine E., Hernandez J.M., Gonzalez-Diaz M., Puente D.A., Velasco G., Freije J.M., Tubio J.M., Royo R., Gelpi J.L., Orozco M., Pisano D.G., Zamora J., Vazquez M., Valencia A., Himmelbauer H., Bayes M., Heath S., Gut M., Gut I., Estivill X., Lopez-Guillermo A., Puente X.S., Campo E., Lopez-Otin C. Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Nat. Genet. 2012, 44:47-52.
105. Wang L., Lawrence M.S., Wan Y., Stojanov P., Sougnez C., Stevenson K., Werner L., Sivachenko A., DeLuca D.S., Zhang L., Zhang W., Vartanov A.R., Fernandes S.M., Goldstein N.R., Folco E.G., Cibulskis K., Tesar B., Sievers Q.L., Shefler E., Gabriel S., Hacohen N., Reed R., Meyerson M., Golub T.R., Lander E.S., Neuberg D., Brown J.R., Getz G., Wu C.J. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N. Engl. J. Med. 2011, 365:2497-2506.
106. Yoshida K., Sanada M., Shiraishi Y., Nowak D., Nagata Y., Yamamoto R., Sato Y., Sato-Otsubo A., Kon A., Nagasaki M., Chalkidis G., Suzuki Y., Shiosaka M., Kawahata R., Yamaguchi T., Otsu M., Obara N., Sakata-Yanagimoto M., Ishiyama K., Mori H., Nolte F., Hofmann W.K., Miyawaki S., Sugano S., Haferlach C., Koeffler H.P., Shih L.Y., Haferlach T., Chiba S., Nakauchi H., Miyano S., Ogawa S. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 2011, 478:64-69.
107. Allo M., Buggiano V., Fededa J.P., Petrillo E., Schor I., de la Mata M., Agirre E., Plass M., Eyras E., Elela S.A., Klinck R., Chabot B., Kornblihtt A.R. Control of alternative splicing through siRNA-mediated transcriptional gene silencing. Nat. Struct. Mol. Biol. 2009, 16:717-724.
108. Elkon R., Ugalde A.P., Agami R. Alternative cleavage and polyadenylation: extent, regulation and function. Nat. Rev. 2013, 14:496-506.
109. Cowley M., Wood A.J., Bohm S., Schulz R., Oakey R.J. Epigenetic control of alternative mRNA processing at the imprinted Herc3/Nap1l5 locus. Nucleic Acids Res. 2012, 40:8917-8926.
110. Wood A.J., Schulz R., Woodfine K., Koltowska K., Beechey C.V., Peters J., Bourc'his D., Oakey R.J. Regulation of alternative polyadenylation by genomic imprinting. Genes Dev. 2008, 22:1141-1146.
111. Lee C.Y., Chen L. Alternative polyadenylation sites reveal distinct chromatin accessibility and histone modification in human cell lines. Bioinformatics 2013, 29:1713-1717.
112. Spies N., Nielsen C.B., Padgett R.A., Burge C.B. Biased chromatin signatures around polyadenylation sites and exons. Mol. Cell 2009, 36:245-254.
113. Ong C.T., Corces V.G. Enhancers: emerging roles in cell fate specification. EMBO Rep. 2012, 13:423-430.
114. Barski A., Cuddapah S., Cui K., Roh T.Y., Schones D.E., Wang Z., Wei G., Chepelev I., Zhao K. High-resolution profiling of histone methylations in the human genome. Cell 2007, 129:823-837.
115. He H.H., Meyer C.A., Shin H., Bailey S.T., Wei G., Wang Q., Zhang Y., Xu K., Ni M., Lupien M., Mieczkowski P., Lieb J.D., Zhao K., Brown M., Liu X.S. Nucleosome dynamics define transcriptional enhancers. Nat. Genet. 2010, 42:343-347.
116. Heintzman N.D., Stuart R.K., Hon G., Fu Y., Ching C.W., Hawkins R.D., Barrera L.O., Van Calcar S., Qu C., Ching K.A., Wang W., Weng Z., Green R.D., Crawford G.E., Ren B. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat. Genet. 2007, 39:311-318.
117. Jin C., Zang C., Wei G., Cui K., Peng W., Zhao K., Felsenfeld G. H3.3/H2A.Z double variant-containing nucleosomes mark 'nucleosome-free regions' of active promoters and other regulatory regions. Nat. Genet. 2009, 41:941-945.
118. Wang Z., Zang C., Rosenfeld J.A., Schones D.E., Barski A., Cuddapah S., Cui K., Roh T.Y., Peng W., Zhang M.Q., Zhao K. Combinatorial patterns of histone acetylations and methylations in the human genome. Nat. Genet. 2008, 40:897-903.
119. Creyghton M.P., Cheng A.W., Welstead G.G., Kooistra T., Carey B.W., Steine E.J., Hanna J., Lodato M.A., Frampton G.M., Sharp P.A., Boyer L.A., Young R.A., Jaenisch R. Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc. Natl. Acad. Sci. U. S. A. 2010, 107:21931-21936.
120. Rada-Iglesias A., Bajpai R., Swigut T., Brugmann S.A., Flynn R.A., Wysocka J. A unique chromatin signature uncovers early developmental enhancers in humans. Nature 2011, 470:279-283.
121. Zentner G.E., Tesar P.J., Scacheri P.C. Epigenetic signatures distinguish multiple classes of enhancers with distinct cellular functions. Genome Res. 2011, 21:1273-1283.
122. Schmidl C., Klug M., Boeld T.J., Andreesen R., Hoffmann P., Edinger M., Rehli M. Lineage-specific DNA methylation in T cells correlates with histone methylation and enhancer activity. Genome Res. 2009, 19:1165-1174.
123. Aran D., Hellman A. DNA methylation of transcriptional enhancers and cancer predisposition. Cell 2013, 154:11-13.
124. Xie M., Hong C., Zhang B., Lowdon R.F., Xing X., Li D., Zhou X., Lee H.J., Maire C.L., Ligon K.L., Gascard P., Sigaroudinia M., Tlsty T.D., Kadlecek T., Weiss A., O'Geen H., Farnham P.J., Madden P.A., Mungall A.J., Tam A., Kamoh B., Cho S., Moore R., Hirst M., Marra M.A., Costello J.F., Wang T. DNA hypomethylation within specific transposable element families associates with tissue-specific enhancer landscape. Nat. Genet. 2013, 45:836-841.
125. Zhang B., Zhou Y., Lin N., Lowdon R.F., Hong C., Nagarajan R.P., Cheng J.B., Li D., Stevens M., Lee H.J., Xing X., Zhou J., Sundaram V., Elliott G., Gu J., Gascard P., Sigaroudinia M., Tlsty T.D., Kadlecek T., Weiss A., O'Geen H., Farnham P.J., Maire C.L., Ligon K.L., Madden P.A., Tam A., Moore R., Hirst M., Marra M.A., Zhang B., Costello J.F., Wang T. Functional DNA methylation differences between tissues, cell types, and across individuals discovered using the M&M algorithm. Genome Res. 2013, (Epub ahead of print).
126. Schubeler D. Molecular biology. Epigenetic islands in a genetic ocean. Science 2012, 338:756-757.
127. Stadler M.B., Murr R., Burger L., Ivanek R., Lienert F., Scholer A., van Nimwegen E., Wirbelauer C., Oakeley E.J., Gaidatzis D., Tiwari V.K., Schubeler D. DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature 2011, 480:490-495.
128. Thurman R.E., Rynes E., Humbert R., Vierstra J., Maurano M.T., Haugen E., Sheffield N.C., Stergachis A.B., Wang H., Vernot B., Garg K., John S., Sandstrom R., Bates D., Boatman L., Canfield T.K., Diegel M., Dunn D., Ebersol A.K., Frum T., Giste E., Johnson A.K., Johnson E.M., Kutyavin T., Lajoie B., Lee B.K., Lee K., London D., Lotakis D., Neph S., Neri F., Nguyen E.D., Qu H., Reynolds A.P., Roach V., Safi A., Sanchez M.E., Sanyal A., Shafer A., Simon J.M., Song L., Vong S., Weaver M., Yan Y., Zhang Z., Zhang Z., Lenhard B., Tewari M., Dorschner M.O., Hansen R.S., Navas P.A., Stamatoyannopoulos G., Iyer V.R., Lieb J.D., Sunyaev S.R., Akey J.M., Sabo P.J., Kaul R., Furey T.S., Dekker J., Crawford G.E., Stamatoyannopoulos J.A. The accessible chromatin landscape of the human genome. Nature 2012, 489:75-82.
129. Popp C., Dean W., Feng S., Cokus S.J., Andrews S., Pellegrini M., Jacobsen S.E., Reik W. Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency. Nature 2010, 463:1101-1105.
130. Rusmintratip V., Sowers L.C. An unexpectedly high excision capacity for mispaired 5-hydroxymethyluracil in human cell extracts. Proc. Natl. Acad. Sci. U. S. A. 2000, 97:14183-14187.
131. Tahiliani M., Koh K.P., Shen Y., Pastor W.A., Bandukwala H., Brudno Y., Agarwal S., Iyer L.M., Liu D.R., Aravind L., Rao A. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 2009, 324:930-935.
132. Bhutani N., Burns D.M., Blau H.M. DNA demethylation dynamics. Cell 2011, 146:866-872.
133. Pastor W.A., Pape U.J., Huang Y., Henderson H.R., Lister R., Ko M., McLoughlin E.M., Brudno Y., Mahapatra S., Kapranov P., Tahiliani M., Daley G.Q., Liu X.S., Ecker J.R., Milos P.M., Agarwal S., Rao A. Genome-wide mapping of 5-hydroxymethylcytosine in embryonic stem cells. Nature 2011, 473:394-397.
134. Serandour A.A., Avner S., Oger F., Bizot M., Percevault F., Lucchetti-Miganeh C., Palierne G., Gheeraert C., Barloy-Hubler F., Peron C.L., Madigou T., Durand E., Froguel P., Staels B., Lefebvre P., Metivier R., Eeckhoute J., Salbert G. Dynamic hydroxymethylation of deoxyribonucleic acid marks differentiation-associated enhancers. Nucleic Acids Res. 2012, 40:8255-8265.
135. Aran D., Sabato S., Hellman A. DNA methylation of distal regulatory sites characterizes dysregulation of cancer genes. Genome Biol. 2013, 14:R21.
136. Hoivik E.A., Bjanesoy T.E., Mai O., Okamoto S., Minokoshi Y., Shima Y., Morohashi K., Boehm U., Bakke M. DNA methylation of intronic enhancers directs tissue-specific expression of steroidogenic factor 1/adrenal 4 binding protein (SF-1/Ad4BP). Endocrinology 2011, 152:2100-2112.
137. Booth M.J., Branco M.R., Ficz G., Oxley D., Krueger F., Reik W., Balasubramanian S. Quantitative sequencing of 5-methylcytosine and 5-hydroxymethylcytosine at single-base resolution. Science 2012, 336:934-937.
138. Yu M., Hon G.C., Szulwach K.E., Song C.X., Zhang L., Kim A., Li X., Dai Q., Shen Y., Park B., Min J.H., Jin P., Ren B., He C. Base-resolution analysis of 5-hydroxymethylcytosine in the mammalian genome. Cell 2012, 149:1368-1380.
139. Wiench M., John S., Baek S., Johnson T.A., Sung M.H., Escobar T., Simmons C.A., Pearce K.H., Biddie S.C., Sabo P.J., Thurman R.E., Stamatoyannopoulos J.A., Hager G.L. DNA methylation status predicts cell type-specific enhancer activity. EMBO J. 2011, 30:3028-3039.
140. Xu J., Pope S.D., Jazirehi A.R., Attema J.L., Papathanasiou P., Watts J.A., Zaret K.S., Weissman I.L., Smale S.T. Pioneer factor interactions and unmethylated CpG dinucleotides mark silent tissue-specific enhancers in embryonic stem cells. Proc. Natl. Acad. Sci. U. S. A. 2007, 104:12377-12382.
141. Xu J., Watts J.A., Pope S.D., Gadue P., Kamps M., Plath K., Zaret K.S., Smale S.T. Transcriptional competence and the active marking of tissue-specific enhancers by defined transcription factors in embryonic and induced pluripotent stem cells. Genes Dev. 2009, 23:2824-2838.
142. Jing H., Vakoc C.R., Ying L., Mandat S., Wang H., Zheng X., Blobel G.A. Exchange of GATA factors mediates transitions in looped chromatin organization at a developmentally regulated gene locus. Mol. Cell 2008, 29:232-242.
143. Palstra R.J., Tolhuis B., Splinter E., Nijmeijer R., Grosveld F., de Laat W. The beta-globin nuclear compartment in development and erythroid differentiation. Nat. Genet. 2003, 35:190-194.
144. Spilianakis C.G., Flavell R.A. Long-range intrachromosomal interactions in the T helper type 2 cytokine locus. Nat. Immunol. 2004, 5:1017-1027.
145. Vernimmen D., De Gobbi M., Sloane-Stanley J.A., Wood W.G., Higgs D.R. Long-range chromosomal interactions regulate the timing of the transition between poised and active gene expression. EMBO J. 2007, 26:2041-2051.
146. Kagey M.H., Newman J.J., Bilodeau S., Zhan Y., Orlando D.A., van Berkum N.L., Ebmeier C.C., Goossens J., Rahl P.B., Levine S.S., Taatjes D.J., Dekker J., Young R.A. Mediator and cohesin connect gene expression and chromatin architecture. Nature 2010, 467:430-435.
147. Zhang H., Niu B., Hu J.F., Ge S., Wang H., Li T., Ling J., Steelman B.N., Qian G., Hoffman A.R. Interruption of intrachromosomal looping by CCCTC binding factor decoy proteins abrogates genomic imprinting of human insulin-like growth factor II. J. Cell Biol. 2011, 193:475-487.
148. Baysal B.E., McKay S.E., Kim Y.J., Zhang Z., Alila L., Willett-Brozick J.E., Pacak K., Kim T.H., Shadel G.S. Genomic imprinting at a boundary element flanking the SDHD locus. Hum. Mol. Genet. 2011, 20:4452-4461.
149. Le May N., Fradin D., Iltis I., Bougneres P., Egly J.M. XPG and XPF endonucleases trigger chromatin looping and DNA demethylation for accurate expression of activated genes. Mol. Cell 2012, 47:622-632.
150. Kim T.K., Hemberg M., Gray J.M., Costa A.M., Bear D.M., Wu J., Harmin D.A., Laptewicz M., Barbara-Haley K., Kuersten S., Markenscoff-Papadimitriou E., Kuhl D., Bito H., Worley P.F., Kreiman G., Greenberg M.E. Widespread transcription at neuronal activity-regulated enhancers. Nature 2010, 465:182-187.
151. Orom U.A., Derrien T., Beringer M., Gumireddy K., Gardini A., Bussotti G., Lai F., Zytnicki M., Notredame C., Huang Q., Guigo R., Shiekhattar R. Long noncoding RNAs with enhancer-like function in human cells. Cell 2010, 143:46-58.
152. Melo C.A., Drost J., Wijchers P.J., van de Werken H., de Wit E., Oude Vrielink J.A., Elkon R., Melo S.A., Leveille N., Kalluri R., de Laat W., Agami R. eRNAs are required for p53-dependent enhancer activity and gene transcription. Mol. Cell 2013, 49:524-535.
153. Irizarry R.A., Ladd-Acosta C., Wen B., Wu Z., Montano C., Onyango P., Cui H., Gabo K., Rongione M., Webster M., Ji H., Potash J.B., Sabunciyan S., Feinberg A.P. The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat. Genet. 2009, 41:178-186.
154. Lee S.T., Xiao Y., Muench M.O., Xiao J., Fomin M.E., Wiencke J.K., Zheng S., Dou X., de Smith A., Chokkalingam A., Buffler P., Ma X., Wiemels J.L. A global DNA methylation and gene expression analysis of early human B-cell development reveals a demethylation signature and transcription factor network. Nucleic Acids Res. 2012, 40:11339-11351.
155. Yu Y., Mo Y., Ebenezer D., Bhattacharyya S., Liu H., Sundaravel S., Giricz O., Wontakal S., Cartier J., Caces B., Artz A., Nischal S., Bhagat T., Bathon K., Maqbool S., Gligich O., Suzuki M., Steidl U., Godley L., Skoultchi A., Greally J., Wickrema A., Verma A. High resolution methylome analysis reveals widespread functional hypomethylation during adult human erythropoiesis. J. Biol. Chem. 2013, 288:8805-8814.
156. Doi A., Park I.H., Wen B., Murakami P., Aryee M.J., Irizarry R., Herb B., Ladd-Acosta C., Rho J., Loewer S., Miller J., Schlaeger T., Daley G.Q., Feinberg A.P. Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts. Nat. Genet. 2009, 41:1350-1353.
157. Deaton A.M., Webb S., Kerr A.R., Illingworth R.S., Guy J., Andrews R., Bird A. Cell type-specific DNA methylation at intragenic CpG islands in the immune system. Genome Res. 2011, 21:1074-1086.
158. Ohm J.E., McGarvey K.M., Yu X., Cheng L., Schuebel K.E., Cope L., Mohammad H.P., Chen W., Daniel V.C., Yu W., Berman D.M., Jenuwein T., Pruitt K., Sharkis S.J., Watkins D.N., Herman J.G., Baylin S.B. A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat. Genet. 2007, 39:237-242.
159. Schlesinger Y., Straussman R., Keshet I., Farkash S., Hecht M., Zimmerman J., Eden E., Yakhini Z., Ben-Shushan E., Reubinoff B.E., Bergman Y., Simon I., Cedar H. Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nat. Genet. 2007, 39:232-236.
160. Widschwendter M., Fiegl H., Egle D., Mueller-Holzner E., Spizzo G., Marth C., Weisenberger D.J., Campan M., Young J., Jacobs I., Laird P.W. Epigenetic stem cell signature in cancer. Nat. Genet. 2007, 39:157-158.
161. Martin-Subero J.I., Kreuz M., Bibikova M., Bentink S., Ammerpohl O., Wickham-Garcia E., Rosolowski M., Richter J., Lopez-Serra L., Ballestar E., Berger H., Agirre X., Bernd H.W., Calvanese V., Cogliatti S.B., Drexler H.G., Fan J.B., Fraga M.F., Hansmann M.L., Hummel M., Klapper W., Korn B., Kuppers R., Macleod R.A., Moller P., Ott G., Pott C., Prosper F., Rosenwald A., Schwaenen C., Schubeler D., Seifert M., Sturzenhofecker B., Weber M., Wessendorf S., Loeffler M., Trumper L., Stein H., Spang R., Esteller M., Barker D., Hasenclever D., Siebert R. New insights into the biology and origin of mature aggressive B-cell lymphomas by combined epigenomic, genomic, and transcriptional profiling. Blood 2009, 113:2488-2497.
162. Duncan B.K., Miller J.H. Mutagenic deamination of cytosine residues in DNA. Nature 1980, 287:560-561.
163. Bock C. Epigenetic biomarker development. Epigenomics 2009, 1:99-110.
164. Heyn H., Esteller M. DNA methylation profiling in the clinic: applications and challenges. Nat. Rev. 2012, 13:679-692.
165. Laird P.W. The power and the promise of DNA methylation markers. Nat. Rev. Cancer 2003, 3:253-266.
166. Hansen K.D., Timp W., Bravo H.C., Sabunciyan S., Langmead B., McDonald O.G., Wen B., Wu H., Liu Y., Diep D., Briem E., Zhang K., Irizarry R.A., Feinberg A.P. Increased methylation variation in epigenetic domains across cancer types. Nat. Genet. 2011, 43:768-775.
167. Kelly T.K., De Carvalho D.D., Jones P.A. Epigenetic modifications as therapeutic targets. Nat. Biotechnol. 2010, 28:1069-1078.
168. Li M., Chen W.D., Papadopoulos N., Goodman S.N., Bjerregaard N.C., Laurberg S., Levin B., Juhl H., Arber N., Moinova H., Durkee K., Schmidt K., He Y., Diehl F., Velculescu V.E., Zhou S., Diaz L.A., Kinzler K.W., Markowitz S.D., Vogelstein B. Sensitive digital quantification of DNA methylation in clinical samples. Nat. Biotechnol. 2009, 27:858-863.
169. Yoo C.B., Jones P.A. Epigenetic therapy of cancer: past, present and future. Nat. Rev. Drug Discov. 2006, 5:37-50.
170. Brennan K., Garcia-Closas M., Orr N., Fletcher O., Jones M., Ashworth A., Swerdlow A., Thorne H., Investigators K.C., Riboli E., Vineis P., Dorronsoro M., Clavel-Chapelon F., Panico S., Onland-Moret N.C., Trichopoulos D., Kaaks R., Khaw K.T., Brown R., Flanagan J.M. Intragenic ATM methylation in peripheral blood DNA as a biomarker of breast cancer risk. Cancer Res. 2012, 72:2304-2313.
171. Raja U.M., Gopal G., Rajkumar T. Intragenic DNA methylation concomitant with repression of ATP4B and ATP4A gene expression in gastric cancer is a potential serum biomarker. Asian Pac. J. Cancer Prev. 2012, 13:5563-5568.
172. Pei L., Choi J.H., Liu J., Lee E.J., McCarthy B., Wilson J.M., Speir E., Awan F., Tae H., Arthur G., Schnabel J.L., Taylor K.H., Wang X., Xu D., Ding H.F., Munn D.H., Caldwell C., Shi H. Genome-wide DNA methylation analysis reveals novel epigenetic changes in chronic lymphocytic leukemia. Epigenetics 2012, 7:567-578.
173. Mayol G., Martin-Subero J.I., Rios J., Queiros A., Kulis M., Sunol M., Esteller M., Gomez S., Garcia I., de Torres C., Rodriguez E., Galvan P., Mora J., Lavarino C. DNA hypomethylation affects cancer-related biological functions and genes relevant in neuroblastoma pathogenesis. PLoS One 2012, 7:e48401.
174. Bernstein B.E., Stamatoyannopoulos J.A., Costello J.F., Ren B., Milosavljevic A., Meissner A., Kellis M., Marra M.A., Beaudet A.L., Ecker J.R., Farnham P.J., Hirst M., Lander E.S., Mikkelsen T.S., Thomson J.A. The NIH Roadmap Epigenomics Mapping Consortium. Nat. Biotechnol. 2010, 28:1045-1048.
175. Adams D., Altucci L., Antonarakis S.E., Ballesteros J., Beck S., Bird A., Bock C., Boehm B., Campo E., Caricasole A., Dahl F., Dermitzakis E.T., Enver T., Esteller M., Estivill X., Ferguson-Smith A., Fitzgibbon J., Flicek P., Giehl C., Graf T., Grosveld F., Guigo R., Gut I., Helin K., Jarvius J., Kuppers R., Lehrach H., Lengauer T., Lernmark A., Leslie D., Loeffler M., Macintyre E., Mai A., Martens J.H., Minucci S., Ouwehand W.H., Pelicci P.G., Pendeville H., Porse B., Rakyan V., Reik W., Schrappe M., Schubeler D., Seifert M., Siebert R., Simmons D., Soranzo N., Spicuglia S., Stratton M., Stunnenberg H.G., Tanay A., Torrents D., Valencia A., Vellenga E., Vingron M., Walter J., Willcocks S. BLUEPRINT to decode the epigenetic signature written in blood. Nat. Biotechnol. 2012, 30:224-226.