Distinct and overlapping control of 5-methylcytosine and 5-hydroxymethylcytosine by the TET proteins in human cancer cells

Genome Biology

Volumn 15, Issue 6, 2014, Pages

  Putiri, Emily L ^a   Tiedemann, Rochelle L ^a,b   Thompson, Joyce J ^a   Liu, Chunsheng ^a   Ho, Thai ^c   Choi, Jeong Hyeon ^b   Robertson, Keith D ^a  

^a MAYO GRADUATE SCHOOL   (United States)

^b MEDICAL COLLEGE OF GEORGIA   (United States)

^c MAYO CLINIC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

5 HYDROXYMETHYLCYTOSINE; 5 METHYLCYTOSINE; CYTOSINE; DIOXYGENASE; HISTONE H3; HISTONE H3K36ME3; HISTONE H3K4ME3; TET PROTEIN; TET1 PROTEIN; TET2 PROTEIN; TET3 PROTEIN; UNCLASSIFIED DRUG; 5-HYDROXYMETHYLCYTOSINE; DNA BINDING PROTEIN; ONCOPROTEIN; TET1 PROTEIN, HUMAN; TET2 PROTEIN, HUMAN; TET3 PROTEIN, HUMAN;

ARTICLE; CANCER CELL; CELL DIFFERENTIATION; CHROMATIN; CONTROLLED STUDY; CPG ISLAND; DNA METHYLATION; EMBRYONAL CARCINOMA STEM CELL; GENE ACTIVATION; GENE EXPRESSION; GENE REPRESSION; HUMAN; HUMAN CELL; PROMOTER REGION; ANALOGS AND DERIVATIVES; DNA SEQUENCE; GENE EXPRESSION REGULATION; GENE SILENCING; GENETIC EPIGENESIS; METABOLISM; PHYSIOLOGY; TUMOR CELL LINE;

5-METHYLCYTOSINE; CELL DIFFERENTIATION; CELL LINE, TUMOR; CYTOSINE; DIOXYGENASES; DNA METHYLATION; DNA-BINDING PROTEINS; EPIGENESIS, GENETIC; GENE EXPRESSION REGULATION, NEOPLASTIC; GENE KNOCKDOWN TECHNIQUES; HUMANS; PROMOTER REGIONS, GENETIC; PROTO-ONCOGENE PROTEINS; SEQUENCE ANALYSIS, DNA;

EID: 84906217278     PISSN: 14747596     EISSN: 1474760X     Source Type: Journal    
DOI: 10.1186/gb-2014-15-6-r81     Document Type: Article

References (76)

1. Jin B, Ernst J, Tiedemann RL, Xu H, Sureshchandra S, Kellis M, Dalton S, Liu C, Choi JH, Robertson KD: Linking DNA methyltransferases to epigenetic marks and nucleosome structure genome-wide in human tumor cells. Cell Rep 2012, 2:1411-1424.
2. Lister R, Pelizzola M, Dowen RH, Hawkins RD, Hon G, Tonti-Filippini J, Nery JR, Lee L, Ye Z, Ngo QM, Edsall L, Antosiewicz-Bourget J, Stewart R, Ruotti V, Millar AH, Thomson JA, Ren B, Ecker JR: Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 2009, 462:315-322.
3. Bird AP: CpG-rich islands and the function of DNA methylation. Nature 1986, 321:209-213.
4. Gardiner-Garden M, Frommer M: CpG islands in vertebrate genomes. J Mol Biol 1987, 196:261-282.
5. Bird A: DNA methylation de novo. Science 1999, 286:2287-2288.
6. Jaenisch R, Bird A: Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 2003, 33:245-254.
7. Irizarry RA, Ladd-Acosta C, Wen B, Wu Z, Montano C, Onyango P, Cui H, Gabo K, Rongione M, Webster M, Ji H, Potash JB, Sabunciyan S, Feinberg AP: The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet 2009, 41:178-186.
8. Bestor TH: Activation of mammalian DNA methyltransferase by cleavage of a Zn binding regulatory domain. EMBO J 1992, 11:2611-2617.
9. Leonhardt H, Page AW, Weier HU, Bestor TH: A targeting sequence directs DNA methyltransferase to sites of DNA replication in mammalian nuclei. Cell 1992, 71:865-873.
10. Okano M, Bell DW, Haber DA, Li E: DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 1999, 99:247-257.
11. Liang G, Chan MF, Tomigahara Y, Tsai YC, Gonzales FA, Li E, Laird PW, Jones PA: Cooperativity between DNA methyltransferases in the maintenance methylation of repetitive elements. Mol Cell Biol 2002, 22:480-491.
12. Yokochi T, Robertson KD: Preferential methylation of unmethylated DNA by mammalian de novo DNA methyltransferase Dnmt3a. J Biol Chem 2002, 277:11735-11745.
13. Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, Agarwal S, Iyer LM, Liu DR, Aravind L, Rao A: Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 2009, 324:930-935.
14. Ito S, D'Alessio AC, Taranova OV, Hong K, Sowers LC, Zhang Y: Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 2010, 466:1129-1133.
15. He YF, Li BZ, Li Z, Liu P, Wang Y, Tang Q, Ding J, Jia Y, Chen Z, Li L, Sun Y, Li X, Dai Q, Song CX, Zhang K, He C, Xu GL: Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 2011, 333:1303-1307.
16. Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA, He C, Zhang Y: Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 2011, 333:1300-1303.
17. Maiti A, Drohat AC: Thymine DNA glycosylase can rapidly excise 5-formylcytosine and 5-carboxylcytosine: potential implications for active demethylation of CpG sites. J Biol Chem 2011, 286:35334-35338.
18. Kriaucionis S, Heintz N: The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science 2009, 324:929-930.
19. Wu H, D'Alessio AC, Ito S, Wang Z, Cui K, Zhao K, Sun YE, Zhang Y: Genome-wide analysis of 5-hydroxymethylcytosine distribution reveals its dual function in transcriptional regulation in mouse embryonic stem cells. Genes Dev 2011, 25:679-684.
20. Williams K, Christensen J, Pedersen MT, Johansen JV, Cloos PA, Rappsilber J, Helin K: TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity. Nature 2011, 473:343-348.
21. Pastor WA, Pape UJ, Huang Y, Henderson HR, Lister R, Ko M, McLoughlin EM, Brudno Y, Mahapatra S, Kapranov P, Tahiliani M, Daley GQ, Liu XS, Ecker JR, Milos PM, Agarwal S, Rao A: Genome-wide mapping of 5-hydroxymethylcytosine in embryonic stem cells. Nature 2011, 473:394-397.
22. Ficz G, Branco MR, Seisenberger S, Santos F, Krueger F, Hore TA, Marques CJ, Andrews S, Reik W: Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation. Nature 2011, 473:398-402.
23. Xu Y, Wu F, Tan L, Kong L, Xiong L, Deng J, Barbera AJ, Zheng L, Zhang H, Huang S, Min J, Nicholson T, Chen T, Xu G, Shi Y, Zhang K, Shi YG: Genome-wide regulation of 5hmC, 5mC, and gene expression by Tet1 hydroxylase in mouse embryonic stem cells. Mol Cell 2011, 42:451-464.
24. Stroud H, Feng S, Morey Kinney S, Pradhan S, Jacobsen SE: 5-Hydroxymethylcytosine is associated with enhancers and gene bodies in human embryonic stem cells. Genome Biol 2011, 12:R54.
25. Yu M, Hon GC, Szulwach KE, Song CX, Zhang L, Kim A, Li X, Dai Q, Shen Y, Park B, Min JH, Jin P, Ren B, He C: Base-resolution analysis of 5-hydroxymethylcytosine in the mammalian genome. Cell 2012, 149:1368-1380.
26. Sun Z, Terragni J, Borgaro JG, Liu Y, Yu L, Guan S, Wang H, Sun D, Cheng X, Zhu Z, Pradhan S, Zheng Y: High-resolution enzymatic mapping of genomic 5-hydroxymethylcytosine in mouse embryonic stem cells. Cell Rep 2013, 3:567-576.
27. YildirimO, Li R, Hung JH, Chen PB, Dong X, Ee LS, Weng Z, Rando OJ, Fazzio TG: Mbd3/NURD complex regulates expression of 5-hydroxymethylcytosine marked genes in embryonic stem cells. Cell 2011, 147:1498-1510.
28. Mellen M, Ayata P, Dewell S, Kriaucionis S, Heintz N: MeCP2 binds to 5hmC enriched within active genes and accessible chromatin in the nervous system. Cell 2012, 151:1417-1430.
29. Spruijt CG, Gnerlich F, Smits AH, Pfaffeneder T, Jansen PW, Bauer C, Munzel M, Wagner M, Muller M, Khan F, Eberl HC, Mensinga A, Brinkman AB, Lephikov K, Muller U, Walter J, Boelens R, van Ingen H, Leonhardt H, Carell T, Vermeulen M: Dynamic readers for 5-(hydroxy)methylcytosine and its oxidized derivatives. Cell 2013, 152:1146-1159.
30. Koh KP, Yabuuchi A, Rao S, Huang Y, CunniffK, Nardone J, Laiho A, Tahiliani M, Sommer CA, Mostoslavsky G, Lahesmaa R, Orkin SH, Rodig SJ, Daley GQ, Rao A: Tet1 and Tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells. Cell Stem Cell 2011, 8:200-213.
31. Dawlaty Meelad M, Ganz K, Powell Benjamin E, Hu Y-C, Markoulaki S, Cheng Albert W, Gao Q, Kim J, Choi S-W, Page David C, Jaenisch R: Tet1 is dispensable for maintaining pluripotency and its loss is compatible with embryonic and postnatal development. Cell Stem Cell 2011, 9:166-175.
32. Dawlaty MM, Breiling A, Le T, Raddatz G, Barrasa MI, Cheng AW, Gao Q, Powell BE, Li Z, Xu M, Faull KF, Lyko F, Jaenisch R: Combined deficiency of Tet1 and Tet2 causes epigenetic abnormalities but is compatible with postnatal development. Dev Cell 2013, 24:310-323.
33. Gu TP, Guo F, Yang H, Wu HP, Xu GF, Liu W, Xie ZG, Shi L, He X, Jin SG, Iqbal K, Shi YG, Deng Z, Szabo PE, Pfeifer GP, Li J, Xu GL: The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes. Nature 2011, 477:606-610.
34. Iqbal K, Jin SG, Pfeifer GP, Szabo PE: Reprogramming of the paternal genome upon fertilization involves genome-wide oxidation of 5-methylcytosine. Proc Natl Acad Sci U S A 2011, 108:3642-3647.
35. Wossidlo M, Nakamura T, Lepikhov K, Marques CJ, Zakhartchenko V, Boiani M, Arand J, Nakano T, Reik W, Walter J: 5-Hydroxymethylcytosine in the mammalian zygote is linked with epigenetic reprogramming. Nat Commun 2011, 2:241.
36. Xu Y, Xu C, Kato A, Tempel W, Abreu JG, Bian C, Hu Y, Hu D, Zhao B, Cerovina T, Diao J, Wu F, He HH, Cui Q, Clark E, Ma C, Barbara A, Veenstra GJ, Xu G, Kaiser UB, Liu XS, Sugrue SP, He X, Min J, Kato Y, Shi YG: Tet3 CXXC domain and dioxygenase activity cooperatively regulate key genes for Xenopus eye and neural development. Cell 2012, 151:1200-1213.
37. Hahn MA, Qiu R, Wu X, Li AX, Zhang H, Wang J, Jui J, Jin SG, Jiang Y, Pfeifer GP, Lu Q: Dynamics of 5-hydroxymethylcytosine and chromatin marks in mammalian neurogenesis. Cell Rep 2013, 3:291-300.
38. Moran-Crusio K, Reavie L, Shih A, Abdel-Wahab O, Ndiaye-Lobry D, Lobry C, Figueroa ME, Vasanthakumar A, Patel J, Zhao X, Perna F, Pandey S, Madzo J, Song C, Dai Q, He C, Ibrahim S, Beran M, Zavadil J, Nimer SD, Melnick A, Godley LA, Aifantis I, Levine RL: Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell 2011, 20:11-24.
39. Quivoron C, Couronne L, Della Valle V, Lopez CK, Plo I, Wagner-Ballon O, Do Cruzeiro M, Delhommeau F, Arnulf B, Stern MH, Godley L, Opolon P, Tilly H, Solary E, Duffourd Y, Dessen P, Merle-Beral H, Nguyen-Khac F, Fontenay M, Vainchenker W, Bastard C, Mercher T, Bernard OA: TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis. Cancer Cell 2011, 20:25-38.
40. Couronne L, Bastard C, Bernard OA: TET2 and DNMT3A mutations in human T-cell lymphoma. N Engl J Med 2012, 366:95-96.
41. Li Z, Cai X, Cai CL, Wang J, Zhang W, Petersen BE, Yang FC, Xu M: Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies. Blood 2011, 118:4509-4518.
42. Abdel-Wahab O, Mullally A, Hedvat C, Garcia-Manero G, Patel J, Wadleigh M, Malinge S, Yao J, Kilpivaara O, Bhat R, Huberman K, Thomas S, Dolgalev I, Heguy A, Paietta E, Le Beau MM, Beran M, Tallman MS, Ebert BL, Kantarjian HM, Stone RM, Gilliland DG, Crispino JD, Levine RL: Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood 2009, 114:144-147.
43. Jin SG, Jiang Y, Qiu R, Rauch TA, Wang Y, Schackert G, Krex D, Lu Q, Pfeifer GP: 5-Hydroxymethylcytosine is strongly depleted in human cancers but its levels do not correlate with IDH1 mutations. Cancer Res 2011, 71:7360-7365.
44. Kudo Y, Tateishi K, Yamamoto K, Yamamoto S, Asaoka Y, Ijichi H, Nagae G, Yoshida H, Aburatani H, Koike K: Loss of 5-hydroxymethylcytosine is accompanied with malignant cellular transformation. Cancer Sci 2012, 103:670-676.
45. Lian CG, Xu Y, Ceol C, Wu F, Larson A, Dresser K, Xu W, Tan L, Hu Y, Zhan Q, Lee CW, Hu D, Lian BQ, Kleffel S, Yang Y, Neiswender J, Khorasani AJ, Fang R, Lezcano C, Duncan LM, Scolyer RA, Thompson JF, Kakavand H, Houvras Y, Zon LI, Mihm MC Jr, Kaiser UB, Schatton T, Woda BA, Murphy GF, et al: Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma. Cell 2012, 150:1135-1146.
46. Yang H, Liu Y, Bai F, Zhang JY, Ma SH, Liu J, Xu ZD, Zhu HG, Ling ZQ, Ye D, Guan KL, Xiong Y: Tumor development is associated with decrease of TET gene expression and 5-methylcytosine hydroxylation. Oncogene 2013, 32:663-669.
47. Ko M, Huang Y, Jankowska AM, Pape UJ, Tahiliani M, Bandukwala HS, An J, Lamperti ED, Koh KP, Ganetzky R, Liu XS, Aravind L, Agarwal S, Maciejewski JP, Rao A: Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature 2010, 468:839-843.
48. Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A, Li Y, Bhagwat N, Vasanthakumar A, Fernandez HF, Tallman MS, Sun Z, Wolniak K, Peeters JK, Liu W, Choe SE, Fantin VR, Paietta E, Lowenberg B, Licht JD, Godley LA, Delwel R, Valk PJ, Thompson CB, Levine RL, Melnick A: Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 2010, 18:553-567.
49. Sperger JM, Chen X, Draper JS, Antosiewicz JE, Chon CH, Jones SB, Brooks JD, Andrews PW, Brown PO, Thomson JA: Gene expression patterns in human embryonic stem cells and human pluripotent germ cell tumors. Proc Natl Acad Sci U S A 2003, 100:13350-13355.
50. Song CX, Szulwach KE, Fu Y, Dai Q, Yi C, Li X, Li Y, Chen CH, Zhang W, Jian X, Wang J, Zhang L, Looney TJ, Zhang B, Godley LA, Hicks LM, Lahn BT, Jin P, He C: Selective chemical labeling reveals the genome-wide distribution of 5-hydroxymethylcytosine. Nat Biotechnol 2011, 29:68-72.
51. Szulwach KE, Li X, Li Y, Song CX, Han JW, Kim S, Namburi S, Hermetz K, Kim JJ, Rudd MK, Yoon YS, Ren B, He C, Jin P: Integrating 5-hydroxymethylcytosine into the epigenomic landscape of human embryonic stem cells. PLoS Genet 2011, 7:e1002154.
52. Huang H, Jiang X, Li Z, Li Y, Song CX, He C, Sun M, Chen P, Gurbuxani S, Wang J, Hong GM, Elkahloun AG, Arnovitz S, Szulwach K, Lin L, Street C, Wunderlich M, Dawlaty M, Neilly MB, Jaenisch R, Yang FC, Mulloy JC, Jin P, Liu PP, Rowley JD, Xu M, Chen J: TET1 plays an essential oncogenic role in MLL-rearranged leukemia. Proc Natl Acad Sci U S A 2013, 110:11994-11999.
53. Bachman KE, Park BH, Rhee I, Rajagopalan H, Herman JG, Baylin SB, Kinzler KW, Vogelstein B: Histone modifications and silencing prior to DNA methylation of a tumor suppressor gene. Cancer Cell 2003, 3:89-95.
54. Freudenberg JM, Ghosh S, Lackford BL, Yellaboina S, Zheng X, Li R, Cuddapah S, Wade PA, Hu G, Jothi R: Acute depletion of Tet1-dependent 5-hydroxymethylcytosine levels impairs LIF/Stat3 signaling and results in loss of embryonic stem cell identity. Nucleic Acids Res 2012, 40:3364-3377.
55. Zang C, Schones DE, Zeng C, Cui K, Zhao K, Peng W: A clustering approach for identification of enriched domains from histone modification ChIP-Seq data. Bioinformatics 2009, 25:1952-1958.
56. Hawkins RD, Hon GC, Lee LK, Ngo Q, Lister R, Pelizzola M, Edsall LE, Kuan S, Luu Y, Klugman S, Antosiewicz-Bourget J, Ye Z, Espinoza C, Agarwahl S, Shen L, Ruotti V, Wang W, Stewart R, Thomson JA, Ecker JR, Ren B: Distinct epigenomic landscapes of pluripotent and lineage-committed human cells. Cell Stem Cell 2010, 6:479-491.
57. Williams K, Christensen J, Helin K: DNA methylation: TET proteins-guardians of CpG islands? EMBO Rep 2012, 13:28-35.
58. Sproul D, Kitchen RR, Nestor CE, Dixon JM, Sims AH, Harrison DJ, Ramsahoye BH, Meehan RR: Tissue of origin determines cancer-associated CpG island promoter hypermethylation patterns. Genome Biol 2012, 13:R84.
59. Wu H, D'Alessio AC, Ito S, Xia K, Wang Z, Cui K, Zhao K, Sun YE, Zhang Y: Dual functions of Tet1 in transcriptional regulation in mouse embryonic stem cells. Nature 2011, 473:389-393.
60. Allen MD, Grummitt CG, Hilcenko C, Min SY, Tonkin LM, Johnson CM, Freund SM, Bycroft M, Warren AJ: Solution structure of the nonmethyl- CpG-binding CXXC domain of the leukaemia-associated MLL histone methyltransferase. EMBO J 2006, 25:4503-4512.
61. Thomson JP, Skene PJ, Selfridge J, Clouaire T, Guy J, Webb S, Kerr ARW, Deaton A, Andrews R, James KD, Turner DJ, Illingworth R, Bird A: CpG islands influence chromatin structure via the CpG-binding protein Cfp1. Nature 2010, 464:1082-1086.
62. Barkess G, West AG: Chromatin insulator elements: establishing barriers to set heterochromatin boundaries. Epigenomics 2012, 4:67-80.
63. Neri F, Incarnato D, Krepelova A, Rapelli S, Pagnani A, Zecchina R, Parlato C, Oliviero S: Genome-wide analysis identifies a functional association of Tet1 and Polycomb repressive complex 2 in mouse embryonic stem cells. Genome Biol 2013, 14:R91.
64. Geiman TM, Sankpal UT, Robertson AK, Chen Y, Mazumdar M, Heale JT, Schmiesing JA, Kim W, Yokomori K, Zhao Y, Robertson KD: Isolation and characterization of a novel DNA methyltransferase complex linking DNMT3B with components of the mitotic chromosome condensation machinery. Nucleic Acids Res 2004, 32:2716-2729.
65. Bostick M, Kim JK, Esteve PO, Clark A, Pradhan S, Jacobsen SE: UHRF1 plays a role in maintaining DNA methylation in mammalian cells. Science 2007, 317:1760-1764.
66. Jin B, Tao Q, Peng J, Soo HM, Wu W, Ying J, Fields CR, Delmas AL, Liu X, Qiu J, Robertson KD: DNA methyltransferase 3B (DNMT3B) mutations in ICF syndrome lead to altered epigenetic modifications and aberrant expression of genes regulating development, neurogenesis and immune function. Hum Mol Genet 2008, 17:690-709.
67. Li H, Durbin R: Fast and accurate short read alignment with Burrows- Wheeler transform. Bioinformatics 2009, 25:1754-1760.
68. Fujita PA, Rhead B, Zweig AS, Hinrichs AS, Karolchik D, Cline MS, Goldman M, Barber GP, Clawson H, Coelho A, Diekhans M, Dreszer TR, Giardine BM, Harte RA, Hillman-Jackson J, Hsu F, Kirkup V, Kuhn RM, Learned K, Li CH, Meyer LR, Pohl A, Raney BJ, Rosenbloom KR, Smith KE, Haussler D, Kent WJ: The UCSC genome browser database: update 2011. Nucleic Acids Res 2011, 39:D876-D882.
69. Weber M, Hellmann I, Stadler MB, 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.
70. Huang DW, Sherman BT, Lempicki RA: Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res 2009, 37:1-13.
71. Yu M, Hon GC, Szulwach KE, Song CX, Jin P, Ren B, He C: Tet-assisted bisulfite sequencing of 5-hydroxymethylcytosine. Nat Protoc 2012, 7:2159-2170.
72. Kumaki Y, Oda M, Okano M: QUMA: quantification tool for methylation analysis. Nucleic Acids Res 2008, 36:W170-W175.
73. Palii SS, Van Emburgh BO, Sankpal UT, Brown KD, Robertson KD: DNA methylation inhibitor 5-aza-2'-deoxycytidine induces reversible genome-wide DNA damage that is distinctly influenced by DNA methyltransferases 1 and 3B. Mol Cell Biol 2008, 28:752-771.
74. Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 2001, 25:402-408.
75. Huang DW, Sherman BT, Lempicki RA: Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 2009, 4:44-57.
76. Widschwendter M, Fiegl H, Egle D, Mueller-Holzner E, Spizzo G, Marth C, Weisenberger DJ, Campan M, Young J, Jacobs I, Laird PW: Epigenetic stem cell signature in cancer. Nat Genet 2007, 39:157-158.