The role of 5-hydroxymethylcytosine in human cancer

Cell and Tissue Research

Volumn 356, Issue 3, 2014, Pages 631-641

  Pfeifer, Gerd P ^a   Xiong, Wenying ^a   Hahn, Maria A ^a   Jin, Seung Gi ^a  

^a CITY OF HOPE NATIONAL MEDICAL CENTER   (United States)

Author keywords

5 Hydroxymethylcytosine; 5 Methylcytosine; Cancer epigenetics; DNA methylation; TET protein

Indexed keywords

5 HYDROXYMETHYLCYTOSINE; 5 METHYLCYTOSINE; ISOCITRATE DEHYDROGENASE 1; ISOCITRATE DEHYDROGENASE 2; 5-HYDROXYMETHYLCYTOSINE; CYTOSINE; DNA;

ASXL1 GENE; CARCINOGENESIS; CPG ISLAND; DISEASE ASSOCIATION; DISEASE MARKER; DNA METHYLATION; DNMT3A GENE; ENZYME METABOLISM; EPIGENETICS; EZH2 GENE; GENE; GENE MUTATION; HUMAN; IDH1 GENE; IDH2 GENE; MLL GENE; NEOPLASM; NONHUMAN; OXIDATION; PRIORITY JOURNAL; PROTEIN DEPLETION; PROTEIN FUNCTION; REVIEW; TET1 GENE; TET2 GENE; ANALOGS AND DERIVATIVES; GENETICS; METABOLISM; OXIDATION REDUCTION REACTION; PATHOLOGY;

CYTOSINE; DNA METHYLATION; DNA, NEOPLASM; HUMANS; NEOPLASMS; OXIDATION-REDUCTION;

EID: 84902298158     PISSN: 0302766X     EISSN: 14320878     Source Type: Journal    
DOI: 10.1007/s00441-014-1896-7     Document Type: Review

References (125)

1. Abdel-Wahab O, Levine RL (2013) Mutations in epigenetic modifiers in the pathogenesis and therapy of acutemyeloid leukemia. Blood 121:3563-3572
2. 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 (2009) Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood 114:144-147
3. Baubec T, Ivanek R, Lienert F, Schubeler D (2013) Methylation-dependent and -independent genomic targeting principles of the MBD protein family. Cell 153:480-492
4. Baylin SB, Jones PA (2011) A decade of exploring the cancer epigenome-biological and translational implications. Nat Rev Cancer 11:726-734
5. Baylin SB, Hoppener JW, de Bustros A, Steenbergh PH, Lips CJ, Nelkin BD (1986) DNA methylation patterns of the calcitonin gene in human lung cancers and lymphomas. Cancer Res 46:2917-2922
6. Blaschke K, Ebata KT, Karimi MM, Zepeda-Martinez JA, Goyal P, Mahapatra S, Tam A, Laird DJ, Hirst M, Rao A, Lorincz MC, Ramalho-Santos M (2013) Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. Nature 500:222-226
7. Castro-Vega LJ, Buffet A, De Cubas AA, Cascon A, Menara M, Khalifa E, Amar L, Azriel S, Bourdeau I, Chabre O, Curras-Freixes M, Franco-Vidal V, Guillaud-Bataille M, Simian C, Morin A, Leton R, Gomez-Grana A, Pollard PJ, Rustin P, Robledo M, Favier J, Gimenez-Roqueplo AP (2014) Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas. Hum Mol Genet 23:2440-2446
8. Chen J, Guo L, Zhang L, Wu H, Yang J, Liu H, Wang X, Hu X, Gu T, Zhou Z, Liu J, Mao SQ, Mo K, Li Y, Lai K, Qi J, Yao H, Pan G, Xu GL, Pei D (2013) Vitamin C modulates TET1 function during somatic cell reprogramming. Nat Genet 45:1504-1509
9. Cheng J, Guo S, Chen S, Mastriano SJ, Liu C, D'Alessio AC, Hysolli E, Guo Y, Yao H, Megyola CM, Li D, Liu J, Pan W, Roden CA, Zhou XL, Heydari K, Chen J, Park IH, Ding Y, Zhang Y, Lu J (2013) An extensive network of TET2-targeting microRNAs regulates malignant hematopoiesis. Cell Rep 5:471-481
10. Costello JF, Fruhwald MC, Smiraglia DJ, Rush LJ, Robertson GP, Gao X, Wright FA, Feramisco JD, Peltomaki P, Lang JC, Schuller DE, Yu L, Bloomfield CD, Caligiuri MA, Yates A, Nishikawa R, Su Huang H, Petrelli NJ, Zhang X, O'Dorisio MS, Held WA, Cavenee WK, Plass C (2000) Aberrant CpG-island methylation has non-random and tumour-type-specific patterns. Nat Genet 24:132-138
11. Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC, Marks KM, Prins RM, Ward PS, Yen KE, Liau LM, Rabinowitz JD, Cantley LC, Thompson CB, Vander Heiden MG, Su SM (2009) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462:739-744
12. Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Masse A, Kosmider O, Le Couedic JP, Robert F, Alberdi A, Lecluse Y, Plo I, Dreyfus FJ, Marzac C, Casadevall N, Lacombe C, Romana SP, Dessen P, Soulier J, Viguie F, Fontenay M, Vainchenker W, Bernard OA (2009) Mutation in TET2 in myeloid cancers. N Engl J Med 360:2289-2301
13. Feinberg AP, Vogelstein B (1983a) Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 301:89-92
14. Feinberg AP, Vogelstein B (1983b) Hypomethylation of ras oncogenes in primary human cancers. Biochem Biophys Res Commun 111:47-54
15. 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 (2010) Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18:553-567
16. Fu X, Jin L, Wang X, Luo A, Hu J, Zheng X, Tsark WM, Riggs AD, Ku HT, Huang W (2013) MicroRNA-26a targets ten eleven translocation enzymes and is regulated during pancreatic cell differentiation. Proc Natl Acad Sci U S A 110:17892-17897
17. Gal-Yam EN, Egger G, Iniguez L, Holster H, Einarsson S, Zhang X, Lin JC, Liang G, Jones PA, Tanay A (2008) Frequent switching of Polycomb repressive marks and DNA hypermethylation in the PC3 prostate cancer cell line. Proc Natl Acad Sci U S A 105:12979-12984
18. Gama-Sosa MA, Slagel VA, Trewyn RW, Oxenhandler R, Kuo KC, Gehrke CW, Ehrlich M (1983) The 5-methylcytosine content of DNA from human tumors. Nucleic Acids Res 11:6883-6894
19. Gambichler T, Sand M, Skrygan M (2013) Loss of 5-hydroxymethylcytosine and ten-eleven translocation 2 protein expression in malignant melanoma. Melanoma Res 23:218-220
20. Globisch D, Munzel M, Muller M, Michalakis S, Wagner M, Koch S, Bruckl T, Biel M, Carell T (2010) Tissue distribution of 5-hydroxymethylcytosine and search for active demethylation intermediates. PLoS One 5:e15367
21. 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 (2011) The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes. Nature 477:606-610
22. Guo JU, Su Y, Zhong C, Ming GL, Song H (2011) Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell 145:423-434
23. Hackett JA, Sengupta R , Zylicz JJ, Murakami K, Lee C, Down TA, Surani MA (2013) Germline DNA demethylation dynamics and imprint erasure through 5-hydroxymethylcytosine. Science 339:448-452
24. Haffner MC, Chaux A, Meeker AK, Esopi DM, Gerber J, Pellakuru LG, Toubaji A, Argani P, Iacobuzio-Donahue C, Nelson WG, Netto GJ, De Marzo AM, Yegnasubramanian S (2011) Global 5-hydroxymethylcytosine content is significantly reduced in tissue stem/progenitor cell compartments and in human cancers. Oncotarget 2:627-637
25. Hahn MA, Hahn T, Lee DH, Esworthy RS, Kim BW, Riggs AD, Chu FF, Pfeifer GP (2008) Methylation of polycomb target genes in intestinal cancer is mediated by inflammation. Cancer Res 68:10280-10289
26. Hahn MA, Qiu R, Wu X, Li AX, Zhang H, Wang J, Jui J, Jin SG, Jiang Y, Pfeifer GP, Lu Q (2013) Dynamics of 5-hydroxymethylcytosine and chromatin marks in mammalian neurogenesis. Cell Rep 3:291-300
27. Hashimoto H, Liu Y, Upadhyay AK, Chang Y, Howerton SB, Vertino PM, Zhang X, Cheng X (2012) Recognition and potential mechanisms for repl ication and erasure of cytosine hydroxymethylation. Nucleic Acids Res 40:4841-4849
28. 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 (2011) Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 333:1303-1307
29. Hou H, Yu H (2010) Structural insights into histone lysine demethylation. Curr Opin Struct Biol 20:739-748
30. Inoue A, Shen L, Dai Q, He C, Zhang Y (2011) Generation and replication-dependent dilution of 5fC and 5caC during mouse pre-implantation development. Cell Res 21:1670-1676
31. Iqbal K, Jin SG, Pfeifer GP, Szabo PE (2011) Reprogramming of the paternal genome upon fertilization involves genome-wide oxidation of 5-methylcytosine. Proc Natl Acad Sci U S A 108:3642-3647
32. Ito S, D'Alessio AC, Taranova OV, Hong K, Sowers LC, Zhang Y (2010) Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 466:1129-1133
33. Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA, He C, Zhang Y (2011) Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333:1300-1303
34. Jankowska AM, Szpurka H, Tiu RV, Makishima H, Afable M, Huh J, O'Keefe CL, Ganetzky R, McDevitt MA, Maciejewski JP (2009) Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms. Blood 113:6403-6410
35. Jin SG, Kadam S, Pfeifer GP (2010) Examination of the specificity of DNA methylation profiling techniques towards 5-methylcytosine and 5-hydroxymethylcytosine. Nucleic Acids Res 38:e125
36. Jin SG, Jiang Y, Qiu R, Rauch TA, Wang Y, Schackert G, Krex D, Lu Q, Pfeifer GP (2011a) 5-Hydroxymethylcytosine is strongly depleted in human cancers but its levels do not correlate with IDH1 mutations. Cancer Res 71:7360-7365
37. Jin SG, Wu X, Li AX, Pfeifer GP (2011b) Genomic mapping of 5-hydroxymethylcytosine in the human brain. Nucleic Acids Res 39:5015-5024
38. Kagiwada S, Kurimoto K, Hirota T, Yamaji M, Saitou M (2013) Replication-coupled passive DNA demethylation for the erasure of genome imprints in mice. EMBO J 32:340-353
39. Kalari S, Jung M, Kernstine KH, Takahashi T, Pfeifer GP (2013) The DNA methylation landscape of small cell lung cancer suggests a differentiation defect of neuroendocrine cells. Oncogene 32:3559-3568
40. Killian JK, Kim SY, Miettinen M, Smith C, Merino M, Tsokos M, Quezado M, Smith WI Jr, Jahromi MS, Xekouki P, Szarek E, Walker RL, Lasota J, Raffeld M, Klotzle B, Wang Z, Jones L, Zhu Y, Wang Y, Waterfall JJ, O'Sullivan MJ, Bibikova M, Pacak K, Stratakis C, Janeway KA, Schiffman JD, Fan JB, Helman L, Meltzer PS (2013) Succinate dehydrogenase mutation underlies global epigenomic divergence in gastrointestinal stromal tumor. Cancer Discov 3:648-657
41. 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 (2010) Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature 468:839-843
42. Ko M, Bandukwala HS, An J, Lamperti ED, Thompson EC, Hastie R, Tsangaratou A, Rajewsky K, Koralov SB, Rao A (2011) Ten-Eleven-Translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice. Proc Natl Acad Sci U S A 108:14566-14571
43. Kohli RM, Zhang Y (2013) TET enzymes, TDG and the dynamics of DNA demethylation. Nature 502:472-479
44. Kosmider O, Gelsi-Boyer V, Cheok M, Grabar S, Della-Valle V, Picard F, Viguie F, Quesnel B, Beyne-Rauzy O, Solary E, Vey N, Hunault-Berger M, Fenaux P, Mansat-De Mas V, Delabesse E, Guardiola P, Lacombe C, Vainchenker W, Preudhomme C, Dreyfus F, Bernard OA, Birnbaum D, Fontenay M (2009) TET2 mutation is an independent favorable prognostic factor in myelodysplastic syndromes (MDSs). Blood 114:3285-3291
45. Kriaucionis S, Heintz N (2009) The nuclear DNA base 5- hydroxymethylcytosine is present in Purkinje neurons and the brain. Science 324:929-930
46. Kudo Y, Tateishi K, Yamamoto K, Yamamoto S, Asaoka Y, Ijichi H, Nagae G, Yoshida H, Aburatani H, Koike K (2012) Loss of 5-hydroxymethylcytosine is accompanied with malignant cellular transformation. Cancer Sci 103:670-676
47. Laird PW (2003) The power and the promise of DNA methylation markers. Nat Rev Cancer 3:253-266
48. Laird A, Thomson JP, Harrison DJ, Meehan RR (2013) 5- hydroxymethylcytosine profiling as an indicator of cellular state. Epigenomics 5:655-669
49. Langemeijer SM, Kuiper RP, Berends M, Knops R, Aslanyan MG, Massop M, Stevens-Linders E, van Hoogen P, van Kessel AG, Raymakers RA, Kamping EJ, Verhoef GE, Verburgh E, Hagemeijer A, Vandenberghe P, de Witte T, van der Reijden BA, Jansen JH (2009) Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat Genet 41:838-842
50. Larson AR, Dresser KA, Zhan Q, Lezcano C, Woda BA, Yosufi B, Thompson JF, Scolyer RA, Mihm MC, Jr., Shi YG, Murphy GF, Lian CG (2014) Loss of 5-hydroxymethylcytosine correlates with increasing morphologic dysplasia in melanocytic tumors. Mod Pathol (in press)
51. Letouze E, Martinelli C, Loriot C, Burnichon N, Abermil N, Ottolenghi C, Janin M, Menara M, Nguyen AT, Benit P, Buffet A, Marcaillou C, Bertherat J, Amar L, Rustin P, De Reynies A, Gimenez-Roqueplo AP, Favier J (2013) SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell 23:739-752
52. Li Z, Cai X, Cai CL, Wang J, Zhang W, Petersen BE, Yang FC, Xu M (2011) Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies. Blood 118:4509-4518
53. 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, Shi YG (2012) Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma. Cell 150:1135-1146
54. Lister R, Mukamel EA, Nery JR, Urich M, Puddifoot CA, Johnson ND, Lucero J, Huang Y, Dwork AJ, Schultz MD, Yu M, Tonti-Filippini J, Heyn H, Hu S, Wu JC, Rao A, Esteller M, He C, Haghighi FG, Sejnowski TJ, Behrens MM, Ecker JR (2013) Global epigenomic reconfiguration during mammalian brain development. Science 341:1237905
55. Liu C, Liu L, Chen X, Shen J, Shan J, Xu Y, Yang Z, Wu L, Xia F, Bie P, Cui Y, Bian XW, Qian C (2013) Decrease of 5-hydroxymethylcytosine is associated with progression of hepatocellular carcinoma through downregulation of TET1. PLoS One 8:e62828
56. Liu S, Dunwell TL, Pfeifer GP, Dunwell JM, Ullah I, Wang Y (2013) Detection of oxidation products of 5-methyl-2′-deoxycytidine in Arabidopsis DNA. PLoS One 8:e84620
57. Lorsbach RB, Moore J, Mathew S, Raimondi SC, Mukatira ST, Downing JR (2003) TET1, a member of a novel protein family, is fused to MLL in acute myeloid leukemia containing the t(10;11)(q22;q23). Leukemia 17:637-641
58. Maiti A, Drohat AC (2011) Thymine DNA glycosylase can rapidly excise 5-formylcytosine and 5-carboxylcytosine: potential implications for active demethylation of CpG sites. J Biol Chem 286:35334-35338
59. Mason EF, Hornick JL (2013) Succinate dehydrogenase deficiency is associated with decreased 5-hydroxymethylcytosine production in gastrointestinal stromal tumors: implications for mechanisms of tumorigenesis. Mod Pathol 26:1492-1497
60. Mayer W, Niveleau A, Walter J, Fundele R, Haaf T (2000) Demethylation of the zygotic paternal genome. Nature 403:501-502
61. Mellen M, Ayata P, Dewell S, Kriaucionis S, Heintz N (2012) MeCP2 binds to 5hmC enriched within active genes and accessible chromatin in the nervous system. Cell 151:1417-1430
62. Minor EA, Court BL, Young JI, Wang G (2013) Ascorbate induces ten-eleven translocation (Tet) methylcytosine dioxygenase-mediated generation of 5-hydroxymethylcytosine. J Biol Chem 288:13669-13674
63. 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 (2011) Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell 20:11-24
64. Münzel M, Globisch D, Bruckl T, Wagner M, Welzmiller V, Michalakis S, Muller M, Biel M, Carell T (2010) Quantification of the sixth DNA base hydroxymethylcytosine in the brain. Angew Chem Int Ed Engl 49:5375-5377
65. Munzel M, Lischke U, Stathis D, Pfaffeneder T, Gnerlich FA, Deiml CA, Koch SC, Karaghiosoff K, Carell T (2011) Improved synthesis and mutagenicity of oligonucleotides containing 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxylcytosine. Chemistry 17:13782-13788
66. Neddermann P, Gallinari P, Lettieri T, Schmid D, Truong O, Hsuan JJ, Wiebauer K, Jiricny J (1996) Cloning and expression of human G/T mismatch-specific thymine-DNA glycosylase. J Biol Chem 271:12767-12774
67. Nejman D, Straussman R, Steinfeld I, Ruvolo M, Roberts D, Yakhini Z, Cedar H (2014) Molecular rules governing de novo methylation in cancer. Cancer Res 74:1475-1483
68. Nestor CE, Ottaviano R, Reddington J, Sproul D, Reinhardt D, Dunican D, Katz E, Dixon JM, Harrison DJ, Meehan RR (2012) Tissue type is a major modifier of the 5-hydroxymethylcytosine content of human genes. Genome Res 22:467-477
69. Noushmehr H, Weisenberger DJ, Diefes K, Phillips HS, Pujara K, Berman BP, Pan F, Pelloski CE, Sulman EP, Bhat KP, Verhaak RG, Hoadley KA, Hayes DN, Perou CM, Schmidt HK, Ding L, Wilson RK, Van Den Berg D, Shen H, Bengtsson H, Neuvial P, Cope LM, Buckley J, Herman JG, Baylin SB, Laird PW, Aldape K (2010) Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17:510-522
70. Ohm JE, McGarvey KM, Yu X, Cheng L, Schuebel KE, Cope L, Mohammad HP, Chen W, Daniel VC, Yu W, Berman DM, Jenuwein T, Pruitt K, Sharkis SJ, Watkins DN, Herman JG, Baylin SB (2007) A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat Genet 39:237-242
71. Ono R, Taki T, Taketani T, Taniwaki M, Kobayashi H, Hayashi Y (2002) LCX, leukemia-associated protein with a CXXC domain, is fused to MLL in acute myeloid leukemia with trilineage dysplasia having t(10;11)(q22;q23). Cancer Res 62:4075-4080
72. Ooi SK, Bestor TH (2008) The colorful history of active DNA demethylation. Cell 133:1145-1148
73. Orr BA, Haffner MC, Nelson WG, Yegnasubramanian S, Eberhart CG (2012) Decreased 5-hydroxymethylcytosine is associated with neural progenitor phenotype in normal brain and shorter survival in malignant glioma. PLoS One 7:e41036
74. Otani J, Kimura H, Sharif J, Endo TA, Mishima Y, Kawakami T, Koseki H, Shirakawa M, Suetake I, Tajima S (2013) Cell cycle-dependent turnover of 5-hydroxymethyl cytosine in mouse embryonic stem cells. PLoS One 8:e82961
75. Pansuriya TC, van Eijk R, d'Adamo P, van Ruler MA, Kuijjer ML, Oosting J, Cleton-Jansen AM, van Oosterwijk JG, Verbeke SL, Meijer D, van Wezel T, Nord KH, Sangiorgi L, Toker B, Liegl-Atzwanger B, San-Julian M, Sciot R, Limaye N, Kindblom LG, Daugaard S, Godfraind C, Boon LM, Vikkula M, Kurek KC, Szuhai K, French PJ, Bovee JV (2011) Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome. Nat Genet 43:1256-1261
76. 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 (2011) Genome-wide mapping of 5-hydroxymethylcytosine in embryonic stem cells. Nature 473:394-397
77. Perez C, Martinez-Calle N, Martin-Subero JI, Segura V, Delabesse E, Fernandez-Mercado M, Garate L, Alvarez S, Rifon J, Varea S, Boultwood J, Wainscoat JS, Cruz Cigudosa J, Calasanz MJ, Cross NC, Prosper F, Agirre X (2012) TET2 mutations are associated with specific 5-methylcytosine and 5-hydroxymethylcytosine profiles in patients with chronic myelomonocytic leukemia. PLoS One 7:e31605
78. Pfeifer GP, Rauch TA, Tommasi S, Besaratinia A, Hahn MA, Iqbal K, Szabó PE, Wu X, Jin S-G (2011) Profiling of modified cytosines in normal and malignant cells. Princess Takamatsu Symp 41:69-72
79. Pfeifer GP, Kadam S, Jin SG (2013) 5-Hydroxymethylcytosine and its potential roles in development and cancer. Epigenetics Chromatin 6:10
80. Polley MY, Leung SC, McShane LM, Gao D, Hugh JC, Mastropasqua MG, Viale G, Zabaglo LA, Penault-Llorca F, Bartlett JM, Gown AM, Symmans WF, Piper T, Mehl E, Enos RA, Hayes DF, Dowsett M, Nielsen TO (2013) An international Ki67 reproducibility study. J Natl Cancer Inst 105:1897-1906
81. 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 (2011) TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis. Cancer Cell 20:25-38
82. Rai K, Huggins IJ, James SR, Karpf AR, Jones DA, Cairns BR (2008) DNA demethylation in zebrafish involves the coupling of a deaminase, a glycosylase, and gadd45. Cell 135:1201-1212
83. Rauch T, Li H, Wu X, Pfeifer GP (2006) MIRA-assisted microarray analysis, a new technology for the determination of DNA methylation patterns, identifies frequent methylation of homeodomain-containing genes in lung cancer cells. Cancer Res 66:7939-7947
84. Rauch T, Wang Z, Zhang X, Zhong X, Wu X, Lau SK, Kernstine KH, Riggs AD, Pfeifer GP (2007) Homeobox gene methylation in lung cancer studied by genome-wide analysis with a microarray-based methylated CpG island recovery assay. Proc Natl Acad Sci U S A 104:5527-5532
85. Rauch TA, Zhong X, Wu X, Wang M, Kernstine KH, Wang Z, Riggs AD, Pfeifer GP (2008) High-resolution mapping of DNA hypermethylation and hypomethylation in lung cancer. Proc Natl Acad Sci U S A 105:252-257
86. Reik W, Dean W, Walter J (2001) Epigenetic reprogramming in mammalian development. Science 293:1089-1093
87. Riggs AD (1975) X inactivation, differentiation, and DNA methylation. Cytogenet Cell Genet 14:9-25
88. Romanov GA, Vanyushin BF (1981)Methylation of reiterated sequences in mammalian DNAs. Effects of the tissue type, age, malignancy and hormonal induction. Biochim Biophys Acta 653:204-218
89. Sasaki M, Knobbe CB, Munger JC, Lind EF, Brenner D, Brustle A, Harris IS, Holmes R, Wakeham A, Haight J, You-Ten A, Li WY, Schalm S, Su SM, Virtanen C, Reifenberger G, Ohashi PS, Barber DL, Figueroa ME, Melnick A, Zuniga-Pflucker JC, Mak TW (2012) IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature 488:656-659
90. Schlesinger Y, Straussman R, Keshet I, Farkash S, Hecht M, Zimmerman J, Eden E, Yakhini Z, Ben-Shushan E, Reubinoff BE, Bergman Y, Simon I, Cedar H (2007) Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nat Genet 39:232-236
91. Seisenberger S, Andrews S, Krueger F, Arand J, Walter J, Santos F, Popp C, Thienpont B, Dean W, Reik W (2012) The dynamics of genome-wide DNA methylation reprogramming in mouse primordial germ cells. Mol Cell 48:849-862
92. 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 (2011) Selective chemical labeling reveals the genome-wide distribution of 5-hydroxymethylcytosine. Nat Biotechnol 29:68-72
93. Song SJ, Ito K, Ala U, Kats L, Webster K, Sun SM, Jongen-Lavrencic M, Manova-Todorova K, Teruya-Feldstein J, Avigan DE, Delwel R, Pandolfi PP (2013a) The oncogenic microRNA miR-22 targets the TET2 tumor suppressor to promote hematopoietic stem cell self-renewal and transformation. Cell Stem Cell 13:87-101
94. Song SJ, Poliseno L, Song MS, Ala U, Webster K, Ng C, Beringer G, Brikbak NJ, Yuan X, Cantley LC, Richardson AL, Pandolfi PP (2013b) MicroRNA-antagonism regulates breast cancer stemness and metastasis via TET-family-dependent chromatin remodeling. Cell 154:311-324
95. Sproul D, Meehan RR (2013) Genomic insights into cancer-associated aberrant CpG island hypermethylation. Brief Funct Genomics 12:174-190
96. Sproul D, Kitchen RR, Nestor CE, Dixon JM, Sims AH, Harrison DJ, Ramsahoye BH, Meehan RR (2012) Tissue of origin determines cancer-associated CpG island promoter hypermethylation patterns. Genome Biol 13:R84
97. Szwagierczak A, Bultmann S, Schmidt CS, Spada F, Leonhardt H (2010) Sensitive enzymatic quantification of 5-hydroxymethylcytosine in genomic DNA. Nucleic Acids Res 38:e181
98. Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, Agarwal S, Iyer LM, Liu DR, Aravind L, Rao A (2009) Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324:930-935
99. Thomson JP, Lempiainen H, Hackett JA, Nestor CE, Muller A, Bolognani F, Oakeley EJ, Schubeler D, Terranova R, Reinhardt D, Moggs JG, Meehan RR (2012) Non-genotoxic carcinogen exposure induces defined changes in the 5-hydroxymethylome. Genome Biol 13:R93
100. Thomson JP, Hunter JM, Lempiainen H, Muller A, Terranova R, Moggs JG, Meehan RR (2013a) Dynamic changes in 5-hydroxymethylation signatures underpin early and late events in drug exposed liver. Nucleic Acids Res 41:5639-5654
101. Thomson JP, Hunter JM, Nestor CE, Dunican DS, Terranova R, Moggs JG, Meehan RR (2013b) Comparative analysis of affinity-based 5-hydroxymethylation enrichment techniques.Nucleic Acids Res 41:e206
102. Timp W, Feinberg AP (2013) Cancer as a dysregulated epigenome allowing cellular growth advantage at the expense of the host. Nat Rev Cancer 13:497-510
103. Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa JP (1999) CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci U S A 96:8681-8686
104. Turcan S, Rohle D, Goenka A, Walsh LA, Fang F, Yilmaz E, Campos C, Fabius AW, Lu C, Ward PS, Thompson CB, Kaufman A, Guryanova O, Levine R, Heguy A, Viale A, Morris LG, Huse JT, Mellinghoff IK, Chan TA (2012) IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483:479-483
105. Uchiyama R, Uhara H, Uchiyama A, Ogawa E, Takazawa Y, Ashida A, Koga H, Hayashi K, Kiniwa Y, Okuyama R (2014) 5-Hydroxymethylcytosine as a useful marker to differentiate between malignant melanomas and benign melanocytic nevi. J Dermatol Sci 73:161-163
106. Ushijima T (2005) Detection and interpretation of altered methylation patterns in cancer cells. Nat Rev Cancer 5:223-231
107. Valinluck V, Sowers LC (2007) Endogenous cytosine damage products alter the site selectivity of human DNA maintenance methyltransferase DNMT1. Cancer Res 67:946-950
108. Vincent JJ, Huang Y, Chen PY, Feng S, Calvopina JH, Nee K, Lee SA, Le T, Yoon AJ, Faull K, Fan G, Rao A, Jacobsen SE, Pellegrini M, Clark AT (2013) Stage-specific roles for tet1 and tet2 in DNA demethylation in primordial germ cells. Cell Stem Cell 12:470-478
109. Widschwendter M, Fiegl H, Egle D, Mueller-Holzner E, Spizzo G, Marth C, Weisenberger DJ, Campan M, Young J, Jacobs I, Laird PW (2007) Epigenetic stem cell signature in cancer. Nat Genet 39:157-158
110. Williams K, Christensen J, Pedersen MT, Johansen JV, Cloos PA, Rappsilber J, Helin K (2011) TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity. Nature 473:343-348
111. Williams K, Christensen J, Helin K (2012) DNA methylation: TET proteins-guardians of CpG islands? EMBO Rep 13:28-35
112. Wossidlo M, Nakamura T, Lepikhov K, Marques CJ, Zakhartchenko V, Boiani M, Arand J, Nakano T, Reik W, Walter J (2011) 5-Hydroxymethylcytosine in the mammalian zygote is linked with epigenetic reprogramming. Nat Commun 2:241
113. Wu SC, Zhang Y (2010) Active DNA demethylation: many roads lead to Rome. Nat Rev Mol Cell Biol 11:607-620
114. Wu X, Rauch TA, Zhong X, Bennett WP, Latif F, Krex D, Pfeifer GP (2010) CpG island hypermethylation in human astrocytomas. Cancer Res 70:2718-2727
115. Xiao M, Yang H, Xu W, Ma S, Lin H, Zhu H, Liu L, Liu Y, Yang C, Xu Y, Zhao S, Ye D, Xiong Y, Guan KL (2012) Inhibition of alpha-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev 26:1326-1338
116. Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, Ito S, Yang C, Xiao MT, Liu LX, Jiang WQ, Liu J, Zhang JY, Wang B, Frye S, Zhang Y, Xu YH, Lei QY, Guan KL, Zhao SM, Xiong Y (2011) Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell 19:17-30
117. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765-773
118. Yang H, Liu Y, Bai F, Zhang JY, Ma SH, Liu J, Xu ZD, Zhu HG, Ling ZQ, Ye D, Guan KL, Xiong Y (2013) Tumor development is associated with decrease of TET gene expression and 5-methylcytosine hydroxylation. Oncogene 32:663-669
119. Yang M, Soga T, Pollard PJ (2013) Oncometabolites: linking altered metabolism with cancer. J Clin Invest 123:3652-3658
120. Yen KE, Bittinger MA, Su SM, Fantin VR (2010) Cancer-associated IDH mutations: biomarker and therapeutic opportunities. Oncogene 29:6409-6417
121. Yildirim O, Li R, Hung JH, Chen PB, Dong X, Ee LS, Weng Z, Rando OJ, Fazzio TG (2011) Mbd3/NURD complex regulates expression of 5- hydroxymethylcytosine marked genes in embryonic stem cells. Cell 147:1498-1510
122. Yu Z, Genest PA, ter Riet B, Sweeney K, DiPaolo C, Kieft R, Christodoulou E, Perrakis A, Simmons JM, Hausinger RP, van Luenen HG, Rigden DJ, Sabatini R, Borst P (2007) The protein that binds to DNA base J in trypanosomatids has features of a thymidine hydroxylase. Nucleic Acids Res 35:2107-2115
123. Yu M, Hon GC, Szulwach KE, Song CX, Jin P, Ren B, He C (2012) Tet-assisted bisulfite sequencing of 5-hydroxymethylcytosine. Nat Protoc 7:2159-2170
124. Zhang L, Lu X, Lu J, Liang H, Dai Q, Xu GL, Luo C, Jiang H, He C (2012) Thymine DNA glycosylase specifically recognizes 5-carboxylcytosine-modified DNA. Nat Chem Biol 8:328-330
125. Zhu JK (2009) Active DNA demethylation mediated by DNA glycosylases. Annu Rev Genet 43:143-166