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Cytosine modifications in neurodevelopment and diseases

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Abstract

DNA methylation has been studied comprehensively and linked to both normal neurodevelopment and neurological diseases. The recent identification of several new DNA modifications, including 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine, has given us a new perspective on the previously observed plasticity in 5mC-dependent regulatory processes. Here, we review the latest research into these cytosine modifications, focusing mainly on their roles in neurodevelopment and diseases.

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References

  1. Holliday R (2006) Epigenetics: a historical overview. Epigenetics 1(2):76–80

    PubMed  Google Scholar 

  2. Waddington CH (1939) An introduction to modern genetics. G. Allen & Unwin, London

    Google Scholar 

  3. Schreiber SL, Bernstein BE (2002) Signaling network model of chromatin. Cell 111(6):771–778

    CAS  PubMed  Google Scholar 

  4. Dupont C, Armant DR, Brenner CA (2009) Epigenetics: definition, mechanisms and clinical perspective. Semin Reprod Med 27(5):351–357. doi:10.1055/s-0029-1237423

    CAS  PubMed Central  PubMed  Google Scholar 

  5. Jaenisch R, Bird A (2003) Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 33(Suppl):245–254. doi:10.1038/ng1089

    CAS  PubMed  Google Scholar 

  6. Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3(6):415–428. doi:10.1038/nrg816

    CAS  PubMed  Google Scholar 

  7. Chi P, Allis CD, Wang GG (2010) Covalent histone modifications—miswritten, misinterpreted and mis-erased in human cancers. Nat Rev Cancer 10(7):457–469. doi:10.1038/nrc2876

    CAS  PubMed Central  PubMed  Google Scholar 

  8. Reik W (2007) Stability and flexibility of epigenetic gene regulation in mammalian development. Nature 447(7143):425–432. doi:10.1038/nature05918

    CAS  PubMed  Google Scholar 

  9. Griffith JS, Mahler HR (1969) DNA ticketing theory of memory. Nature 223(5206):580–582

    CAS  PubMed  Google Scholar 

  10. Suzuki MM, Bird A (2008) DNA methylation landscapes: provocative insights from epigenomics. Nat Rev Genet 9(6):465–476. doi:10.1038/nrg2341

    CAS  PubMed  Google Scholar 

  11. Li E (2002) Chromatin modification and epigenetic reprogramming in mammalian development. Nat Rev Genet 3(9):662–673. doi:10.1038/nrg887

    CAS  PubMed  Google Scholar 

  12. Gopalakrishnan S, Van Emburgh BO, Robertson KD (2008) DNA methylation in development and human disease. Mutat Res 647(1–2):30–38. doi:10.1016/j.mrfmmm.2008.08.006

    CAS  PubMed Central  PubMed  Google Scholar 

  13. Jakovcevski M, Akbarian S (2012) Epigenetic mechanisms in neurological disease. Nat Med 18(8):1194–1204. doi:10.1038/nm.2828

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Ma DK, Marchetto MC, Guo JU, Ming GL, Gage FH, Song H (2010) Epigenetic choreographers of neurogenesis in the adult mammalian brain. Nat Neurosci 13(11):1338–1344. doi:10.1038/nn.2672

    CAS  PubMed Central  PubMed  Google Scholar 

  15. Baylin SB, Jones PA (2011) A decade of exploring the cancer epigenome—biological and translational implications. Nat Rev Cancer 11(10):726–734. doi:10.1038/nrc3130

    CAS  PubMed Central  PubMed  Google Scholar 

  16. Okano M, Bell DW, Haber DA, Li E (1999) DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99(3):247–257

    CAS  PubMed  Google Scholar 

  17. Bestor TH (2000) The DNA methyltransferases of mammals. Hum Mol Genet 9(16):2395–2402

    CAS  PubMed  Google Scholar 

  18. Anderson RM, Bosch JA, Goll MG, Hesselson D, Dong PD, Shin D, Chi NC, Shin CH, Schlegel A, Halpern M, Stainier DY (2009) Loss of Dnmt1 catalytic activity reveals multiple roles for DNA methylation during pancreas development and regeneration. Dev Biol 334(1):213–223. doi:10.1016/j.ydbio.2009.07.017

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Sun LQ, Lee DW, Zhang Q, Xiao W, Raabe EH, Meeker A, Miao D, Huso DL, Arceci RJ (2004) Growth retardation and premature aging phenotypes in mice with disruption of the SNF2-like gene, PASG. Genes Dev 18(9):1035–1046. doi:10.1101/gad.1176104

    CAS  PubMed  Google Scholar 

  20. Hendrich B, Bird A (1998) Identification and characterization of a family of mammalian methyl-CpG binding proteins. Mol Cell Biol 18(11):6538–6547

    CAS  PubMed Central  PubMed  Google Scholar 

  21. Bogdanovic O, Veenstra GJ (2009) DNA methylation and methyl-CpG binding proteins: developmental requirements and function. Chromosoma 118(5):549–565. doi:10.1007/s00412-009-0221-9

    CAS  PubMed Central  PubMed  Google Scholar 

  22. Lopez-Serra L, Esteller M (2008) Proteins that bind methylated DNA and human cancer: reading the wrong words. Br J Cancer 98(12):1881–1885. doi:10.1038/sj.bjc.6604374

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Chahrour M, Jung SY, Shaw C, Zhou X, Wong ST, Qin J, Zoghbi HY (2008) MeCP2, a key contributor to neurological disease, activates and represses transcription. Science 320(5880):1224–1229. doi:10.1126/science.1153252

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Guy J, Cheval H, Selfridge J, Bird A (2011) The role of MeCP2 in the brain. Annu Rev Cell Dev Biol 27:631–652. doi:10.1146/annurev-cellbio-092910-154121

    CAS  PubMed  Google Scholar 

  25. Wyatt GR, Cohen SS (1953) The bases of the nucleic acids of some bacterial and animal viruses: the occurrence of 5-hydroxymethylcytosine. Biochem J 55(5):774–782

    CAS  PubMed  Google Scholar 

  26. Penn NW, Suwalski R, O’Riley C, Bojanowski K, Yura R (1972) The presence of 5-hydroxymethylcytosine in animal deoxyribonucleic acid. Biochem J 126(4):781–790

    CAS  PubMed  Google Scholar 

  27. 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(5929):930–935. doi:10.1126/science.1170116

    CAS  PubMed Central  PubMed  Google Scholar 

  28. 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(7310):1129–1133. doi:10.1038/nature09303

    CAS  PubMed Central  PubMed  Google Scholar 

  29. 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(6047):1303–1307. doi:10.1126/science.1210944

    CAS  PubMed Central  PubMed  Google Scholar 

  30. 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(6047):1300–1303. doi:10.1126/science.1210597

    CAS  PubMed Central  PubMed  Google Scholar 

  31. 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(7):1417–1430. doi:10.1016/j.cell.2012.11.022

    CAS  PubMed Central  PubMed  Google Scholar 

  32. Szulwach KE, Li X, Li Y, Song CX, Wu H, Dai Q, Irier H, Upadhyay AK, Gearing M, Levey AI, Vasanthakumar A, Godley LA, Chang Q, Cheng X, He C, Jin P (2011) 5-hmC-mediated epigenetic dynamics during postnatal neurodevelopment and aging. Nat Neurosci 14(12):1607–1616. doi:10.1038/nn.2959

    CAS  PubMed Central  PubMed  Google Scholar 

  33. 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(1):68–72. doi:10.1038/nbt.1732

    CAS  PubMed Central  PubMed  Google Scholar 

  34. Kriaucionis S, Heintz N (2009) The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science 324(5929):929–930. doi:10.1126/science.1169786

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Munzel 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 49(31):5375–5377. doi:10.1002/anie.201002033

    Google Scholar 

  36. 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(7347):394–397. doi:10.1038/nature10102

    CAS  PubMed Central  PubMed  Google Scholar 

  37. 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 (2011) Integrating 5-hydroxymethylcytosine into the epigenomic landscape of human embryonic stem cells. PLoS Genet 7(6):e1002154. doi:10.1371/journal.pgen.1002154

    CAS  PubMed Central  PubMed  Google Scholar 

  38. 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 (2012) Base-resolution analysis of 5-hydroxymethylcytosine in the mammalian genome. Cell 149(6):1368–1380. doi:10.1016/j.cell.2012.04.027

    CAS  PubMed Central  PubMed  Google Scholar 

  39. Feng J, Zhou Y, Campbell SL, Le T, Li E, Sweatt JD, Silva AJ, Fan G (2010) Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons. Nat Neurosci 13(4):423–430. doi:10.1038/nn.2514

    CAS  PubMed Central  PubMed  Google Scholar 

  40. Miller CA, Sweatt JD (2007) Covalent modification of DNA regulates memory formation. Neuron 53(6):857–869. doi:10.1016/j.neuron.2007.02.022

    CAS  PubMed  Google Scholar 

  41. Feng J, Chang H, Li E, Fan G (2005) Dynamic expression of de novo DNA methyltransferases Dnmt3a and Dnmt3b in the central nervous system. J Neurosci Res 79(6):734–746. doi:10.1002/jnr.20404

    CAS  PubMed  Google Scholar 

  42. Goto K, Numata M, Komura JI, Ono T, Bestor TH, Kondo H (1994) Expression of DNA methyltransferase gene in mature and immature neurons as well as proliferating cells in mice. Differentiation 56(1–2):39–44

    CAS  PubMed  Google Scholar 

  43. Li E, Bestor TH, Jaenisch R (1992) Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69(6):915–926

    CAS  PubMed  Google Scholar 

  44. Golshani P, Hutnick L, Schweizer F, Fan G (2005) Conditional Dnmt1 deletion in dorsal forebrain disrupts development of somatosensory barrel cortex and thalamocortical long-term potentiation. Thalamus Relat Syst 3(3):227–233. doi:10.1017/S1472928807000222

    CAS  PubMed Central  PubMed  Google Scholar 

  45. Nguyen S, Meletis K, Fu D, Jhaveri S, Jaenisch R (2007) Ablation of de novo DNA methyltransferase Dnmt3a in the nervous system leads to neuromuscular defects and shortened lifespan. Dev Dyn 236(6):1663–1676. doi:10.1002/dvdy.21176

    CAS  PubMed  Google Scholar 

  46. Wu H, Coskun V, Tao J, Xie W, Ge W, Yoshikawa K, Li E, Zhang Y, Sun YE (2010) Dnmt3a-dependent nonpromoter DNA methylation facilitates transcription of neurogenic genes. Science 329(5990):444–448. doi:10.1126/science.1190485

    CAS  PubMed Central  PubMed  Google Scholar 

  47. Fan G, Martinowich K, Chin MH, He F, Fouse SD, Hutnick L, Hattori D, Ge W, Shen Y, Wu H, ten Hoeve J, Shuai K, Sun YE (2005) DNA methylation controls the timing of astrogliogenesis through regulation of JAK-STAT signaling. Development 132(15):3345–3356. doi:10.1242/dev.01912

    CAS  PubMed  Google Scholar 

  48. Jones PA, Baylin SB (2007) The epigenomics of cancer. Cell 128(4):683–692. doi:10.1016/j.cell.2007.01.029

    CAS  PubMed  Google Scholar 

  49. Esteller M (2008) Epigenetics in cancer. N Engl J Med 358(11):1148–1159. doi:10.1056/NEJMra072067

    CAS  PubMed  Google Scholar 

  50. 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(2):132–138. doi:10.1038/72785

    CAS  PubMed  Google Scholar 

  51. Robertson KD (2005) DNA methylation and human disease. Nat Rev Genet 6(8):597–610. doi:10.1038/nrg1655

    CAS  PubMed  Google Scholar 

  52. Urdinguio RG, Sanchez-Mut JV, Esteller M (2009) Epigenetic mechanisms in neurological diseases: genes, syndromes, and therapies. Lancet Neurol 8(11):1056–1072. doi:10.1016/S1474-4422(09)70262-5

    CAS  PubMed  Google Scholar 

  53. Sproul D, Meehan RR (2013) Genomic insights into cancer-associated aberrant CpG island hypermethylation. Brief Funct Genomics 12(3):174–190. doi:10.1093/bfgp/els063

    CAS  PubMed  Google Scholar 

  54. Klein CJ, Botuyan MV, Wu Y, Ward CJ, Nicholson GA, Hammans S, Hojo K, Yamanishi H, Karpf AR, Wallace DC, Simon M, Lander C, Boardman LA, Cunningham JM, Smith GE, Litchy WJ, Boes B, Atkinson EJ, Middha S, BD PJ, Parisi JE, Mer G, Smith DI, Dyck PJ (2011) Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss. Nat Genet 43(6):595–600. doi:10.1038/ng.830

    CAS  PubMed Central  PubMed  Google Scholar 

  55. Easwaran HP, Schermelleh L, Leonhardt H, Cardoso MC (2004) Replication-independent chromatin loading of Dnmt1 during G2 and M phases. EMBO Rep 5(12):1181–1186. doi:10.1038/sj.embor.7400295

    CAS  PubMed Central  PubMed  Google Scholar 

  56. Winkelmann J, Lin L, Schormair B, Kornum BR, Faraco J, Plazzi G, Melberg A, Cornelio F, Urban AE, Pizza F, Poli F, Grubert F, Wieland T, Graf E, Hallmayer J, Strom TM, Mignot E (2012) Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy. Hum Mol Genet 21(10):2205–2210. doi:10.1093/hmg/dds035

    CAS  PubMed  Google Scholar 

  57. Xu GL, Bestor TH, Bourc’his D, Hsieh CL, Tommerup N, Bugge M, Hulten M, Qu X, Russo JJ, Viegas-Pequignot E (1999) Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature 402(6758):187–191. doi:10.1038/46052

    CAS  PubMed  Google Scholar 

  58. Hansen RS, Wijmenga C, Luo P, Stanek AM, Canfield TK, Weemaes CM, Gartler SM (1999) The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. Proc Natl Acad Sci USA 96(25):14412–14417

    CAS  PubMed  Google Scholar 

  59. Jin B, Tao Q, Peng J, Soo HM, Wu W, Ying J, Fields CR, Delmas AL, Liu X, Qiu J, Robertson KD (2008) 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 17(5):690–709. doi:10.1093/hmg/ddm341

    CAS  PubMed  Google Scholar 

  60. de Greef JC, Wang J, Balog J, den Dunnen JT, Frants RR, Straasheijm KR, Aytekin C, van der Burg M, Duprez L, Ferster A, Gennery AR, Gimelli G, Reisli I, Schuetz C, Schulz A, Smeets DF, Sznajer Y, Wijmenga C, van Eggermond MC, Van Ostaijen-Ten Dam MM, Lankester AC, van Tol MJ, van den Elsen PJ, Weemaes CM, van der Maarel SM (2011) Mutations in ZBTB24 are associated with immunodeficiency, centromeric instability, and facial anomalies syndrome type 2. Am J Hum Genet 88(6):796–804. doi:10.1016/j.ajhg.2011.04.018

    PubMed Central  PubMed  Google Scholar 

  61. Chouery E, Abou-Ghoch J, Corbani S, El Ali N, Korban R, Salem N, Castro C, Klayme S, Azoury-Abou Rjeily M, Khoury-Matar R, Debo G, Germanos-Haddad M, Delague V, Lefranc G, Megarbane A (2012) A novel deletion in ZBTB24 in a Lebanese family with immunodeficiency, centromeric instability, and facial anomalies syndrome type 2. Clin Genet 82(5):489–493. doi:10.1111/j.1399-0004.2011.01783.x

    CAS  PubMed  Google Scholar 

  62. Hou HA, Kuo YY, Liu CY, Chou WC, Lee MC, Chen CY, Lin LI, Tseng MH, Huang CF, Chiang YC, Lee FY, Liu MC, Liu CW, Tang JL, Yao M, Huang SY, Ko BS, Hsu SC, Wu SJ, Tsay W, Chen YC, Tien HF (2012) DNMT3A mutations in acute myeloid leukemia: stability during disease evolution and clinical implications. Blood 119(2):559–568. doi:10.1182/blood-2011-07-369934

    CAS  PubMed  Google Scholar 

  63. Ley TJ, Ding L, Walter MJ, McLellan MD, Lamprecht T, Larson DE, Kandoth C, Payton JE, Baty J, Welch J, Harris CC, Lichti CF, Townsend RR, Fulton RS, Dooling DJ, Koboldt DC, Schmidt H, Zhang Q, Osborne JR, Lin L, O’Laughlin M, McMichael JF, Delehaunty KD, McGrath SD, Fulton LA, Magrini VJ, Vickery TL, Hundal J, Cook LL, Conyers JJ, Swift GW, Reed JP, Alldredge PA, Wylie T, Walker J, Kalicki J, Watson MA, Heath S, Shannon WD, Varghese N, Nagarajan R, Westervelt P, Tomasson MH, Link DC, Graubert TA, DiPersio JF, Mardis ER, Wilson RK (2010) DNMT3A mutations in acute myeloid leukemia. N Engl J Med 363(25):2424–2433. doi:10.1056/NEJMoa1005143

    CAS  PubMed Central  PubMed  Google Scholar 

  64. Zhao X, Ueba T, Christie BR, Barkho B, McConnell MJ, Nakashima K, Lein ES, Eadie BD, Willhoite AR, Muotri AR, Summers RG, Chun J, Lee KF, Gage FH (2003) Mice lacking methyl-CpG binding protein 1 have deficits in adult neurogenesis and hippocampal function. Proc Natl Acad Sci USA 100(11):6777–6782. doi:10.1073/pnas.1131928100

    CAS  PubMed  Google Scholar 

  65. Li X, Barkho BZ, Luo Y, Smrt RD, Santistevan NJ, Liu C, Kuwabara T, Gage FH, Zhao X (2008) Epigenetic regulation of the stem cell mitogen Fgf-2 by Mbd1 in adult neural stem/progenitor cells. J Biol Chem 283(41):27644–27652. doi:10.1074/jbc.M804899200

    CAS  PubMed  Google Scholar 

  66. Lewis JD, Meehan RR, Henzel WJ, Maurer-Fogy I, Jeppesen P, Klein F, Bird A (1992) Purification, sequence, and cellular localization of a novel chromosomal protein that binds to methylated DNA. Cell 69(6):905–914

    CAS  PubMed  Google Scholar 

  67. Shahbazian MD, Antalffy B, Armstrong DL, Zoghbi HY (2002) Insight into Rett syndrome: MeCP2 levels display tissue- and cell-specific differences and correlate with neuronal maturation. Hum Mol Genet 11(2):115–124

    CAS  PubMed  Google Scholar 

  68. Chahrour M, Zoghbi HY (2007) The story of Rett syndrome: from clinic to neurobiology. Neuron 56(3):422–437. doi:10.1016/j.neuron.2007.10.001

    CAS  PubMed  Google Scholar 

  69. Skene PJ, Illingworth RS, Webb S, Kerr AR, James KD, Turner DJ, Andrews R, Bird AP (2010) Neuronal MeCP2 is expressed at near histone-octamer levels and globally alters the chromatin state. Mol Cell 37(4):457–468. doi:10.1016/j.molcel.2010.01.030

    CAS  PubMed  Google Scholar 

  70. Boyes J, Bird A (1991) DNA methylation inhibits transcription indirectly via a methyl-CpG binding protein. Cell 64(6):1123–1134

    CAS  PubMed  Google Scholar 

  71. Nan X, Campoy FJ, Bird A (1997) MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin. Cell 88(4):471–481

    CAS  PubMed  Google Scholar 

  72. Ben-Shachar S, Chahrour M, Thaller C, Shaw CA, Zoghbi HY (2009) Mouse models of MeCP2 disorders share gene expression changes in the cerebellum and hypothalamus. Hum Mol Genet 18(13):2431–2442. doi:10.1093/hmg/ddp181

    CAS  PubMed  Google Scholar 

  73. Horike S, Cai S, Miyano M, Cheng JF, Kohwi-Shigematsu T (2005) Loss of silent-chromatin looping and impaired imprinting of DLX5 in Rett syndrome. Nat Genet 37(1):31–40. doi:10.1038/ng1491

    CAS  PubMed  Google Scholar 

  74. Young JI, Hong EP, Castle JC, Crespo-Barreto J, Bowman AB, Rose MF, Kang D, Richman R, Johnson JM, Berget S, Zoghbi HY (2005) Regulation of RNA splicing by the methylation-dependent transcriptional repressor methyl-CpG binding protein 2. Proc Natl Acad Sci USA 102(49):17551–17558. doi:10.1073/pnas.0507856102

    CAS  PubMed  Google Scholar 

  75. Adler DA, Quaderi NA, Brown SD, Chapman VM, Moore J, Tate P, Disteche CM (1995) The X-linked methylated DNA binding protein, Mecp2, is subject to X inactivation in the mouse. Mamm Genome 6(8):491–492

    CAS  PubMed  Google Scholar 

  76. Schule B, Armstrong DD, Vogel H, Oviedo A, Francke U (2008) Severe congenital encephalopathy caused by MECP2 null mutations in males: central hypoxia and reduced neuronal dendritic structure. Clin Genet 74(2):116–126. doi:10.1111/j.1399-0004.2008.01005.x

    CAS  PubMed  Google Scholar 

  77. Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY (1999) Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 23(2):185–188. doi:10.1038/13810

    CAS  PubMed  Google Scholar 

  78. Ramocki MB, Peters SU, Tavyev YJ, Zhang F, Carvalho CM, Schaaf CP, Richman R, Fang P, Glaze DG, Lupski JR, Zoghbi HY (2009) Autism and other neuropsychiatric symptoms are prevalent in individuals with MeCP2 duplication syndrome. Ann Neurol 66(6):771–782. doi:10.1002/ana.21715

    CAS  PubMed Central  PubMed  Google Scholar 

  79. Zhou Z, Hong EJ, Cohen S, Zhao WN, Ho HY, Schmidt L, Chen WG, Lin Y, Savner E, Griffith EC, Hu L, Steen JA, Weitz CJ, Greenberg ME (2006) Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation. Neuron 52(2):255–269. doi:10.1016/j.neuron.2006.09.037

    CAS  PubMed  Google Scholar 

  80. Cohen S, Gabel HW, Hemberg M, Hutchinson AN, Sadacca LA, Ebert DH, Harmin DA, Greenberg RS, Verdine VK, Zhou Z, Wetsel WC, West AE, Greenberg ME (2011) Genome-wide activity-dependent MeCP2 phosphorylation regulates nervous system development and function. Neuron 72(1):72–85. doi:10.1016/j.neuron.2011.08.022

    CAS  PubMed Central  PubMed  Google Scholar 

  81. Guy J, Gan J, Selfridge J, Cobb S, Bird A (2007) Reversal of neurological defects in a mouse model of Rett syndrome. Science 315(5815):1143–1147. doi:10.1126/science.1138389

    CAS  PubMed  Google Scholar 

  82. Giacometti E, Luikenhuis S, Beard C, Jaenisch R (2007) Partial rescue of MeCP2 deficiency by postnatal activation of MeCP2. Proc Natl Acad Sci USA 104(6):1931–1936. doi:10.1073/pnas.0610593104

    CAS  PubMed  Google Scholar 

  83. 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(7):1498–1510. doi:10.1016/j.cell.2011.11.054

    CAS  PubMed Central  PubMed  Google Scholar 

  84. 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 (2013) Dynamic readers for 5-(hydroxy)methylcytosine and its oxidized derivatives. Cell 152(5):1146–1159. doi:10.1016/j.cell.2013.02.004

    CAS  PubMed  Google Scholar 

  85. Muotri AR, Gage FH (2006) Generation of neuronal variability and complexity. Nature 441(7097):1087–1093. doi:10.1038/nature04959

    CAS  PubMed  Google Scholar 

  86. Muotri AR, Chu VT, Marchetto MC, Deng W, Moran JV, Gage FH (2005) Somatic mosaicism in neuronal precursor cells mediated by L1 retrotransposition. Nature 435(7044):903–910. doi:10.1038/nature03663

    CAS  PubMed  Google Scholar 

  87. Coufal NG, Garcia-Perez JL, Peng GE, Yeo GW, Mu Y, Lovci MT, Morell M, O’Shea KS, Moran JV, Gage FH (2009) L1 retrotransposition in human neural progenitor cells. Nature 460(7259):1127–1131. doi:10.1038/nature08248

    CAS  PubMed Central  PubMed  Google Scholar 

  88. Gatchel JR, Zoghbi HY (2005) Diseases of unstable repeat expansion: mechanisms and common principles. Nat Rev Genet 6(10):743–755. doi:10.1038/nrg1691

    CAS  PubMed  Google Scholar 

  89. La Spada AR, Taylor JP (2010) Repeat expansion disease: progress and puzzles in disease pathogenesis. Nat Rev Genet 11(4):247–258. doi:10.1038/nrg2748

    PubMed  Google Scholar 

  90. Jin P, Duan R, Qurashi A, Qin Y, Tian D, Rosser TC, Liu H, Feng Y, Warren ST (2007) Pur alpha binds to rCGG repeats and modulates repeat-mediated neurodegeneration in a Drosophila model of fragile X tremor/ataxia syndrome. Neuron 55(4):556–564. doi:10.1016/j.neuron.2007.07.020

    CAS  PubMed Central  PubMed  Google Scholar 

  91. Sofola OA, Jin P, Qin Y, Duan R, Liu H, de Haro M, Nelson DL, Botas J (2007) RNA-binding proteins hnRNP A2/B1 and CUGBP1 suppress fragile X CGG premutation repeat-induced neurodegeneration in a Drosophila model of FXTAS. Neuron 55(4):565–571. doi:10.1016/j.neuron.2007.07.021

    CAS  PubMed Central  PubMed  Google Scholar 

  92. Ng CW, Yildirim F, Yap YS, Dalin S, Matthews BJ, Velez PJ, Labadorf A, Housman DE, Fraenkel E (2013) Extensive changes in DNA methylation are associated with expression of mutant huntingtin. Proc Natl Acad Sci USA 110(6):2354–2359. doi:10.1073/pnas.1221292110

    CAS  PubMed  Google Scholar 

  93. Cleary JD, Pearson CE (2003) The contribution of cis-elements to disease-associated repeat instability: clinical and experimental evidence. Cytogenet Genome Res 100(1–4):25–55. doi:72837

    CAS  PubMed  Google Scholar 

  94. Verkerk AJ, Pieretti M, Sutcliffe JS, Fu YH, Kuhl DP, Pizzuti A, Reiner O, Richards S, Victoria MF, Zhang FP et al (1991) Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65(5):905–914

    CAS  PubMed  Google Scholar 

  95. Jin P, Alisch RS, Warren ST (2004) RNA and microRNAs in fragile X mental retardation. Nat Cell Biol 6(11):1048–1053. doi:10.1038/ncb1104-1048

    CAS  PubMed  Google Scholar 

  96. Oberle I, Rousseau F, Heitz D, Kretz C, Devys D, Hanauer A, Boue J, Bertheas MF, Mandel JL (1991) Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome. Science 252(5009):1097–1102

    CAS  PubMed  Google Scholar 

  97. Williams K, Christensen J, Helin K (2012) DNA methylation: TET proteins-guardians of CpG islands? EMBO Rep 13(1):28–35. doi:10.1038/embor.2011.233

    CAS  PubMed Central  Google Scholar 

  98. Tan L, Shi YG (2012) Tet family proteins and 5-hydroxymethylcytosine in development and disease. Development 139(11):1895–1902. doi:10.1242/dev.070771

    CAS  PubMed  Google Scholar 

  99. Branco MR, Ficz G, Reik W (2012) Uncovering the role of 5-hydroxymethylcytosine in the epigenome. Nat Rev Genet 13(1):7–13. doi:10.1038/nrg3080

    CAS  Google Scholar 

  100. Cimmino L, Abdel-Wahab O, Levine RL, Aifantis I (2011) TET family proteins and their role in stem cell differentiation and transformation. Cell Stem Cell 9(3):193–204. doi:10.1016/j.stem.2011.08.007

    CAS  PubMed Central  PubMed  Google Scholar 

  101. Pfaffeneder T, Hackner B, Truss M, Munzel M, Muller M, Deiml CA, Hagemeier C, Carell T (2011) The discovery of 5-formylcytosine in embryonic stem cell DNA. Angew Chem 50(31):7008–7012. doi:10.1002/anie.201103899

    CAS  Google Scholar 

  102. 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(3):423–434. doi:10.1016/j.cell.2011.03.022

    CAS  PubMed Central  PubMed  Google Scholar 

  103. 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(4):328–330. doi:10.1038/nchembio.914

    CAS  PubMed Central  PubMed  Google Scholar 

  104. Hashimoto H, Liu Y, Upadhyay AK, Chang Y, Howerton SB, Vertino PM, Zhang X, Cheng X (2012) Recognition and potential mechanisms for replication and erasure of cytosine hydroxymethylation. Nucleic Acids Res 40(11):4841–4849. doi:10.1093/nar/gks155

    CAS  PubMed Central  PubMed  Google Scholar 

  105. Inoue A, Shen L, Dai Q, He C, Zhang Y (2011) Generation and replication-dependent dilution of 5fC and 5caC during mouse preimplantation development. Cell Res 21(12):1670–1676. doi:10.1038/cr.2011.189

    CAS  PubMed  Google Scholar 

  106. Mayer W, Niveleau A, Walter J, Fundele R, Haaf T (2000) Demethylation of the zygotic paternal genome. Nature 403(6769):501–502. doi:10.1038/35000654

    CAS  PubMed  Google Scholar 

  107. Oswald J, Engemann S, Lane N, Mayer W, Olek A, Fundele R, Dean W, Reik W, Walter J (2000) Active demethylation of the paternal genome in the mouse zygote. Curr Biol 10(8):475–478

    CAS  PubMed  Google Scholar 

  108. 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(7366):606–610. doi:10.1038/nature10443

    CAS  PubMed  Google Scholar 

  109. 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. doi:10.1016/j.stem.2013.01.016

    PubMed  Google Scholar 

  110. Hackett JA, Sengupta R, Zylicz JJ, Murakami K, Lee C, Down TA, Surani MA (2012) Germline DNA demethylation dynamics and imprint erasure through 5-hydroxymethylcytosine. Science. doi:10.1126/science.1229277

    PubMed Central  Google Scholar 

  111. Kress C, Thomassin H, Grange T (2001) Local DNA demethylation in vertebrates: how could it be performed and targeted? FEBS Lett 494(3):135–140

    CAS  PubMed  Google Scholar 

  112. Barreto G, Schafer A, Marhold J, Stach D, Swaminathan SK, Handa V, Doderlein G, Maltry N, Wu W, Lyko F, Niehrs C (2007) Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation. Nature 445(7128):671–675. doi:10.1038/nature05515

    CAS  PubMed  Google Scholar 

  113. Ma DK, Jang MH, Guo JU, Kitabatake Y, Chang ML, Pow-Anpongkul N, Flavell RA, Lu B, Ming GL, Song H (2009) Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis. Science 323(5917):1074–1077. doi:10.1126/science.1166859

    CAS  PubMed Central  PubMed  Google Scholar 

  114. Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, Ito S, Yang C, Wang P, 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(1):17–30. doi:10.1016/j.ccr.2010.12.014

    CAS  PubMed Central  PubMed  Google Scholar 

  115. Losman JA, Looper R, Koivunen P, Lee S, Schneider RK, McMahon C, Cowley G, Root D, Ebert BL, Kaelin WG Jr (2013) (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science. doi:10.1126/science.1231677

    PubMed Central  PubMed  Google Scholar 

  116. Liang DC, Liu HC, Yang CP, Jaing TH, Hung IJ, Yeh TC, Chen SH, Hou JY, Huang YJ, Shih YS, Huang YH, Lin TH, Shih LY (2013) Cooperating gene mutations in childhood acute myeloid leukemia with special reference on mutations of ASXL1, TET2, IDH1, IDH2 and DNMT3A. Blood. doi:10.1182/blood-2012-06-436782

    Google Scholar 

  117. 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(6):1135–1146. doi:10.1016/j.cell.2012.07.033

    CAS  PubMed Central  PubMed  Google Scholar 

  118. Gorovets D, Kannan K, Shen R, Kastenhuber ER, Islamdoust N, Campos C, Pentsova E, Heguy A, Jhanwar SC, Mellinghoff IK, Chan TA, Huse JT (2012) IDH mutation and neuroglial developmental features define clinically distinct subclasses of lower grade diffuse astrocytic glioma. Clin Cancer Res 18(9):2490–2501. doi:10.1158/1078-0432.CCR-11-2977

    CAS  PubMed  Google Scholar 

  119. Vella P, Scelfo A, Jammula S, Chiacchiera F, Williams K, Cuomo A, Roberto A, Christensen J, Bonaldi T, Helin K, Pasini D (2013) Tet proteins connect the O-linked N-acetylglucosamine transferase Ogt to chromatin in embryonic stem cells. Mol Cell. doi:10.1016/j.molcel.2012.12.019

    PubMed  Google Scholar 

  120. Deplus R, Delatte B, Schwinn MK, Defrance M, Mendez J, Murphy N, Dawson MA, Volkmar M, Putmans P, Calonne E, Shih AH, Levine RL, Bernard O, Mercher T, Solary E, Urh M, Daniels DL, Fuks F (2013) TET2 and TET3 regulate GlcNAcylation and H3K4 methylation through OGT and SET1/COMPASS. EMBO J. doi:10.1038/emboj.2012.357

    PubMed  Google Scholar 

  121. Chen Q, Chen Y, Bian C, Fujiki R, Yu X (2012) TET2 promotes histone O-GlcNAcylation during gene transcription. Nature. doi:10.1038/nature11742

    Google Scholar 

  122. Francisco H, Kollins K, Varghis N, Vocadlo D, Vosseller K, Gallo G (2009) O-GLcNAc post-translational modifications regulate the entry of neurons into an axon branching program. Dev Neurobiol 69(2–3):162–173. doi:10.1002/dneu.20695

    CAS  PubMed Central  PubMed  Google Scholar 

  123. Liu Y, Li X, Yu Y, Shi J, Liang Z, Run X, Li Y, Dai CL, Grundke-Iqbal I, Iqbal K, Liu F, Gong CX (2012) Developmental regulation of protein O-GlcNAcylation, O-GlcNAc transferase, and O-GlcNAcase in mammalian brain. PLoS ONE 7(8):e43724. doi:10.1371/journal.pone.0043724

    CAS  PubMed Central  PubMed  Google Scholar 

  124. 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. doi:10.1016/j.celrep.2013.01.011

    PubMed Central  Google Scholar 

  125. 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 (2012) Tet3 CXXC domain and dioxygenase activity cooperatively regulate key genes for Xenopus Eye and neural development. Cell 151(6):1200–1213. doi:10.1016/j.cell.2012.11.014

    CAS  PubMed Central  PubMed  Google Scholar 

  126. Costa Y, Ding J, Theunissen TW, Faiola F, Hore TA, Shliaha PV, Fidalgo M, Saunders A, Lawrence M, Dietmann S, Das S, Levasseur DN, Li Z, Xu M, Reik W, Silva JC, Wang J (2013) NANOG-dependent function of TET1 and TET2 in establishment of pluripotency. Nature. doi:10.1038/nature11925

    PubMed Central  Google Scholar 

  127. Doege CA, Inoue K, Yamashita T, Rhee DB, Travis S, Fujita R, Guarnieri P, Bhagat G, Vanti WB, Shih A, Levine RL, Nik S, Chen EI, Abeliovich A (2012) Early-stage epigenetic modification during somatic cell reprogramming by Parp1 and Tet2. Nature 488(7413):652–655. doi:10.1038/nature11333

    CAS  PubMed  Google Scholar 

  128. 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(7347):343–348. doi:10.1038/nature10066

    CAS  PubMed Central  PubMed  Google Scholar 

  129. 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 (2011) Genome-wide regulation of 5hmC, 5mC, and gene expression by Tet1 hydroxylase in mouse embryonic stem cells. Mol Cell 42(4):451–464. doi:10.1016/j.molcel.2011.04.005

    CAS  PubMed Central  PubMed  Google Scholar 

  130. Koh KP, Yabuuchi A, Rao S, Huang Y, Cunniff K, Nardone J, Laiho A, Tahiliani M, Sommer CA, Mostoslavsky G, Lahesmaa R, Orkin SH, Rodig SJ, Daley GQ, Rao A (2011) Tet1 and Tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells. Cell Stem Cell 8(2):200–213. doi:10.1016/j.stem.2011.01.008

    CAS  PubMed Central  PubMed  Google Scholar 

  131. Dawlaty MM, Ganz K, Powell BE, Hu YC, Markoulaki S, Cheng AW, Gao Q, Kim J, Choi SW, Page DC, Jaenisch R (2011) Tet1 is dispensable for maintaining pluripotency and its loss is compatible with embryonic and postnatal development. Cell Stem Cell 9(2):166–175. doi:10.1016/j.stem.2011.07.010

    CAS  PubMed Central  PubMed  Google Scholar 

  132. 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 (2013) Combined deficiency of Tet1 and Tet2 causes epigenetic abnormalities but is compatible with postnatal development. Dev Cell. doi:10.1016/j.devcel.2012.12.015

    PubMed  Google Scholar 

  133. Wang F, Yang Y, Lin X, Wang JQ, Wu YS, Xie W, Wang D, Zhu S, Liao YQ, Sun Q, Yang YG, Guo C, Han C, Tang TS (2013) Genome-wide loss of 5-hmC is a novel epigenetic feature of huntington’s disease. Hum Mol Genet. doi:10.1093/hmg/ddt214

    Google Scholar 

  134. Song CX, Szulwach KE, Dai Q, Fu Y, Mao SQ, Lin L, Street C, Li Y, Poidevin M, Wu H, Gao J, Liu P, Li L, Xu GL, Jin P, He C (2013) Genome-wide profiling of 5-formylcytosine reveals its roles in epigenetic priming. Cell. doi:10.1016/j.cell.2013.04.001

    Google Scholar 

  135. Shen L, Wu H, Diep D, Yamaguchi S, D’Alessio AC, Fung HL, Zhang K, Zhang Y (2013) Genome-wide analysis reveals TET- and TDG-dependent 5-methylcytosine oxidation dynamics. Cell. doi:10.1016/j.cell.2013.04.002

    PubMed Central  Google Scholar 

  136. 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(7325):839–843. doi:10.1038/nature09586

    CAS  PubMed Central  PubMed  Google Scholar 

  137. 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(1):11–24. doi:10.1016/j.ccr.2011.06.001

    CAS  PubMed Central  PubMed  Google Scholar 

  138. 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 USA 108(35):14566–14571. doi:10.1073/pnas.1112317108

    CAS  PubMed  Google Scholar 

  139. 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. doi:10.1074/jbc.C113.464800

    Google Scholar 

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Acknowledgments

The authors would like to thank C. Strauss for critical reading of the manuscript. P.J. is supported by NIH grants (NS079625/NS051630/HD073162/AG025688 to P.J.), and the Simons Foundation Autism Research Initiative (P.J.).

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  1. Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Suite 301, Atlanta, GA, 30322, USA

    Bing Yao & Peng Jin

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Yao, B., Jin, P. Cytosine modifications in neurodevelopment and diseases. Cell. Mol. Life Sci. 71, 405–418 (2014). https://doi.org/10.1007/s00018-013-1433-y

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