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Cytosine hydroxymethylation by TET enzymes: From the control of gene expression to the regulation of DNA repair mechanisms, and back

Univ Rennes, CNRS, IGDR-UMR 6290, F35000 Rennes, France

Chromatin is a complex multi-scale structure composed of DNA wrapped around nucleosomes. The compaction state is finely regulated mainly by epigenetic marks present not only on nucleosomes but also on the DNA itself. The most studied DNA post-transcriptional modification is 5-methylcytosine (5-mC). Methylation of the cytosine at CpG islands localized at the promoter is associated with repression of transcription. On the contrary, enrichment of 5-hydroxymethylcytosine (5-hmC), one of the oxidation products of 5-mC by TET (ten-eleven translocation) enzymes, on promoters and enhancers promotes transcription activation. Recently, a new role of 5-hmC has been proposed in the context of DNA repair. 5-hmC was found to be enriched at DNA lesions and knockdown of TET led to impaired repair efficiency. Here, we review our current knowledge regarding the role of the regulation of the 5-mC/5-hmC balance by TET enzymes in the context of transcription modulation as well as DNA repair processes. In a final section, we speculate on the potential involvement of TET proteins in DNA repair mechanisms associated with transcription activation.
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Keywords chromatin; DNA repair; transcription; ten eleven translocation; 5-hydroxymethylcytosine

Citation: Audrey Lejart, Gilles Salbert, Sébastien Huet. Cytosine hydroxymethylation by TET enzymes: From the control of gene expression to the regulation of DNA repair mechanisms, and back. AIMS Biophysics, 2018, 5(3): 182-193. doi: 10.3934/biophy.2018.3.182


  • 1. Geiman TM, Robertson KD (2002) Chromatin remodeling, histone modifications, and DNA methylation-how does it all fit together? J Cell Biochem 87: 117–125.    
  • 2. Bonev B, Cavalli G (2016) Organization and function of the 3D genome. Nat Rev Genet 17: 661–678.    
  • 3. Bannister AJ, Kouzarides T (2011) Regulation of chromatin by histone modifications. Cell Res 21: 381–395.    
  • 4. Tessarz P, Kouzarides T (2014) Histone core modifications regulating nucleosome structure and dynamics. Nat Rev Mol Cell Bio 15: 703–708.
  • 5. Koch A, Joosten SC, Feng Z, et al. (2018) Analysis of DNA methylation in cancer: Location revisited. Nat Rev Clin Oncol 15: 459–466.    
  • 6. Watt F, Molloy PL (1988) Cytosine methylation prevents binding to DNA of a HeLa cell transcription factor required for optimal expression of the adenovirus major late promoter. Gene Dev 2: 1136–1143.    
  • 7. Csankovszki G, Nagy A, Jaenisch R (2001) Synergism of Xist RNA, DNA methylation, and histone hypoacetylation in maintaining X chromosome inactivation. J Cell Biol 153: 773–784.    
  • 8. Li E, Beard C, Jaenisch R (1993) Role for DNA methylation in genomic imprinting. Nature 366: 362–365.    
  • 9. Okano M, Bell DW, Haber DA, et al. (1999) DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99: 247–257.    
  • 10. Hashimoto H, Liu Y, Upadhyay AK, et al. (2012) Recognition and potential mechanisms for replication and erasure of cytosine hydroxymethylation. Nucleic Acids Res 40: 4841–4849.    
  • 11. Nabel CS, Jia H, Ye Y, et al. (2012) AID/APOBEC deaminases disfavor modified cytosines implicated in DNA demethylation. Nat Chem Biol 8: 751–758.    
  • 12. Bochtler M, Kolano A, Xu GL (2017) DNA demethylation pathways: Additional players and regulators. Bioessays 39: 1–13.    
  • 13. Tahiliani M, Koh KP, Shen Y, et al. (2009) Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324: 930–935.    
  • 14. Tamanaha E, Guan S, Marks K, et al. (2016) Distributive processing by the iron(II)/α-ketoglutarate-dependent catalytic domains of the TET enzymes is consistent with epigenetic roles for oxidized 5-methylcytosine bases. J Am Chem Soc 138: 9345–9348.    
  • 15. Müller U, Bauer C, Siegl M, et al. (2014) TET-mediated oxidation of methylcytosine causes TDG or NEIL glycosylase dependent gene reactivation. Nucleic Acids Res 42: 8592–8604.    
  • 16. Weber AR, Krawczyk C, Robertson AB, et al. (2016) Biochemical reconstitution of TET1-TDG-BER-dependent active DNA demethylation reveals a highly coordinated mechanism. Nat Commun 7: 10806.    
  • 17. Wang J, Hevi S, Kurash JK, et al. (2009) The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation. Nat Genet 41: 125–129.    
  • 18. Szwagierczak A, Bultmann S, Schmidt CS, et al. (2010) Sensitive enzymatic quantification of 5-hydroxymethylcytosine in genomic DNA. Nucleic Acids Res 38: e181.    
  • 19. Spruijt CG, Gnerlich F, Smits AH, et al. (2013) Dynamic readers for 5-(hydroxy)methylcytosine and its oxidized derivatives. Cell 152: 1146–1159.    
  • 20. Matarese F, Carrillode SPE, Stunnenberg HG (2011) 5-Hydroxymethylcytosine: A new kid on the epigenetic block? Mol Syst Biol 7: 562.
  • 21. Koh KP, Yabuuchi A, Rao S, et al. (2011) Tet1 and Tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells. Cell Stem Cell 8: 200–213.    
  • 22. Ito S, D'Alessio AC, Taranova OV, et al. (2010) Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 466: 1129–1133.    
  • 23. Caron G, Hussein M, Kulis M, et al. (2015) Cell-cycle-dependent reconfiguration of the DNA methylome during terminal differentiation of human B cells into plasma cells. Cell Rep 13: 1059–1071.    
  • 24. Costa Y, Ding J, Theunissen TW, et al. (2013) NANOG-dependent function of TET1 and TET2 in establishment of pluripotency. Nature 495: 370–374.    
  • 25. Kriaucionis S, Heintz N (2009) The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science 324: 929–930.    
  • 26. Jin SG, Wu X, Li AX, et al. (2011) Genomic mapping of 5-hydroxymethylcytosine in the human brain. Nucleic Acids Res 39: 5015–5024.    
  • 27. Nestor CE, Ottaviano R, Reddington J, et al. (2012) Tissue type is a major modifier of the 5-hydroxymethylcytosine content of human genes. Genome Res 22: 467–477.    
  • 28. Szulwach KE, Li X, Li Y, et al. (2011) 5-hmC-mediated epigenetic dynamics during postnatal neurodevelopment and aging. Nat Neurosci 14: 1607–1616.    
  • 29. Sherwani SI, Khan HA (2015) Role of 5-hydroxymethylcytosine in neurodegeneration. Gene 570: 17–24.    
  • 30. Jeschke J, Collignon E, Fuks F (2016) Portraits of TET-mediated DNA hydroxymethylation in cancer. Curr Opin Genet Dev 36: 16–26.    
  • 31. Haffner MC, Chaux A, Meeker AK, et al. (2011) Global 5-hydroxymethylcytosine content is significantly reduced in tissue stem/progenitor cell compartments and in human cancers. Oncotarget 2: 627–637.
  • 32. Mahé EA, Madigou T, Sérandour AA, et al. (2017) Cytosine modifications modulate the chromatin architecture of transcriptional enhancers. Genome Res 27: 947–958.    
  • 33. Nan X, Ng HH, Johnson CA, et al. (1998) Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393: 386–389.    
  • 34. Ng HH, Bird A (1999) DNA methylation and chromatin modification. Curr Opin Genet Dev 9: 158–163.    
  • 35. Schübeler D (2015) Function and information content of DNA methylation. Nature 517: 321–326.    
  • 36. Williams K, Christensen J, Pedersen MT, et al. (2011) TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity. Nature 473: 343–348.    
  • 37. Sérandour AA, Avner S, Oger F, et al. (2012) Dynamic hydroxymethylation of deoxyribonucleic acid marks differentiation-associated enhancers. Nucleic Acids Res 40: 8255–8265.    
  • 38. Song CX, He C (2013) Potential functional roles of DNA demethylation intermediates. Trends Biochem Sci 38: 480–484.    
  • 39. Sepulveda H, Villagra A, Montecino M (2017) Tet-mediated DNA demethylation is required for SWI/SNF-dependent chromatin remodeling and histone-modifying activities that trigger expression of the Sp7 osteoblast master gene during mesenchymal lineage commitment. Mol Cell Biol 37.
  • 40. Yildirim O, Li R, Hung JH, et al. (2011) Mbd3/NURD complex regulates expression of 5-hydroxymethylcytosine marked genes in embryonic stem cells. Cell 147: 1498–1510.    
  • 41. Neri F, Incarnato D, Krepelova A, et al. (2013) Genome-wide analysis identifies a functional association of Tet1 and Polycomb repressive complex 2 in mouse embryonic stem cells. Genome Biol 14: R91.    
  • 42. Deplus R, Delatte B, Schwinn MK, et al. (2013) TET2 and TET3 regulate GlcNAcylation and H3K4 methylation through OGT and SET1/COMPASS. EMBO J 32: 645–655.    
  • 43. Kong L, Tan L, Lv R, et al. (2016) A primary role of TET proteins in establishment and maintenance of De Novo bivalency at CpG islands. Nucleic Acids Res 44: 8682–8692.    
  • 44. Mendonca A, Chang EH, Liu W, et al. (2014) Hydroxymethylation of DNA influences nucleosomal conformation and stability in vitro. BBA-Gene Regul Mech 1839: 1323–1329.
  • 45. Deplus R, Delatte B, Schwinn MK, et al. (2013) TET2 and TET3 regulate GlcNAcylation and H3K4 methylation through OGT and SET1/COMPASS. EMBO J 32: 645–655.    
  • 46. Guan W, Guyot R, Samarut J, et al. (2017) Methylcytosine dioxygenase TET3 interacts with thyroid hormone nuclear receptors and stabilizes their association to chromatin. P Natl Acad Sci USA 114: 8229–8234.    
  • 47. Zhang YW, Wang Z, Xie W, et al. (2017) Acetylation enhances TET2 function in protecting against abnormal DNA methylation during oxidative stress. Mol Cell 65: 323–335.    
  • 48. Cimmino L, Dawlaty MM, Ndiaye-Lobry D, et al. (2015) TET1 is a tumor suppressor of hematopoietic malignancy. Nat Immunol 16: 653–662.    
  • 49. An J, González-Avalos E, Chawla A, et al. (2015) Acute loss of TET function results in aggressive myeloid cancer in mice. Nat Commun 6: 10071.    
  • 50. Kafer GR, Li X, Horii T, et al. (2016) 5-Hydroxymethylcytosine marks sites of DNA damage and promotes genome stability. Cell Rep 14: 1283–1292.    
  • 51. Mahfoudhi E, Talhaoui I, Cabagnols X, et al. (2016) TET2-mediated 5-hydroxymethylcytosine induces genetic instability and mutagenesis. DNA Rep 43: 78–88.    
  • 52. Jiang D, Zhang Y, Hart RP, et al. (2015) Alteration in 5-hydroxymethylcytosine-mediated epigenetic regulation leads to Purkinje cell vulnerability in ATM deficiency. Brain 138: 3520–3536.    
  • 53. Jiang D, Wei S, Chen F, et al. (2017) TET3-mediated DNA oxidation promotes ATR-dependent DNA damage response. EMBO Rep 18: 781–796.    
  • 54. Blackford AN, Jackson SP (2017) ATM, ATR, and DNA-PK: the trinity at the heart of the DNA damage response. Mol Cell 66: 801–817.    
  • 55. Sellou H, Lebeaupin T, Chapuis C, et al. (2016) The poly(ADP-ribose)-dependent chromatin remodeler Alc1 induces local chromatin relaxation upon DNA damage. Mol Biol Cell 27: 3791–3799.    
  • 56. Smith R, Sellou H, Chapuis C, et al. (2018) CHD3 and CHD4 recruitment and chromatin remodeling activity at DNA breaks is promoted by early poly(ADP-ribose)-dependent chromatin relaxation. Nucleic Acids Res 46: 6087.
  • 57. Ciccarone F, Valentini E, Zampieri M, et al. (2015) 5mC-hydroxylase activity is influenced by the PARylation of TET1 enzyme. Oncotarget 6: 24333–24347.
  • 58. Ciccarone F, Valentini E, Bacalini MG, et al. (2014) Poly(ADP-ribosyl)ation is involved in the epigenetic control of TET1 gene transcription. Oncotarget 5: 10356–10367.
  • 59. Chou DM, Adamson B, Dephoure NE, et al. (2010) A chromatin localization screen reveals poly (ADP ribose)-regulated recruitment of the repressive polycomb and NuRD complexes to sites of DNA damage. P Natl Acad Sci USA 107: 18475–18480.    
  • 60. Luijsterburg MS, Dinant C, Lans H, et al. (2009) Heterochromatin protein 1 is recruited to various types of DNA damage. J Cell Biol 185: 577–586.    
  • 61. Abu-Zhayia ER, Awwad SW, Ben-Oz B, et al. (2017) CDYL1 fosters double-strand break-induced transcription silencing and promotes homology-directed repair. J Mol Cell Biol 1: 1.
  • 62. D'Alessandro G, Fagagna FDD (2017) Transcription and DNA damage: holding hands or crossing swords? J Mol Biol 429: 3215–3229.    
  • 63. Puc J, Aggarwal AK, Rosenfeld MG (2017) Physiological functions of programmed DNA breaks in signal-induced transcription. Nat Rev Mol Cell Bio 18: 471–476.
  • 64. Ju BG, Lunyak VV, Perissi V, et al. (2006) A topoisomerase IIbeta-mediated dsDNA break required for regulated transcription. Science 312: 1798–1802.    
  • 65. Madabhushi R, Gao F, Pfenning AR, et al. (2015) Activity-induced DNA breaks govern the expression of neuronal early-response genes. Cell 161: 1592–1605.    
  • 66. Perillo B, Ombra MN, Bertoni A, et al. (2008) DNA oxidation as triggered by H3K9me2 demethylation drives estrogen-induced gene expression. Science 319: 202–206.    
  • 67. Puc J, Kozbial P, Li W, et al. (2015) Ligand-dependent enhancer activation regulated by topoisomerase-I activity. Cell 160: 367–380.    
  • 68. Baranello L, Wojtowicz D, Cui K, et al. (2016) RNA polymerase II regulates topoisomerase 1 activity to favor efficient transcription. Cell 165: 357–371.    
  • 69. Bunch H, Lawney BP, Lin YF, et al. (2015) Transcriptional elongation requires DNA break-induced signalling. Nat Commun 6: 10191.    
  • 70. Marnef A, Cohen S, Legube G (2017) Transcription-coupled DNA double-strand break repair: active genes need special care. J Mol Biol 429: 1277–1288.    
  • 71. Huertas P, Aguilera A (2003) Cotranscriptionally formed DNA:RNA hybrids mediate transcription elongation impairment and transcription-associated recombination. Mol Cell 12: 711–721.    
  • 72. Sollier J, Stork CT, García-Rubio ML, et al. (2014) Transcription-coupled nucleotide excision repair factors promote R-loop-induced genome instability. Mol Cell 56: 777–785.    
  • 73. Métivier R, Gallais R, Tiffoche C, et al. (2008) Cyclical DNA methylation of a transcriptionally active promoter. Nature 452: 45–50.    
  • 74. Li J, Wu X, Zhou Y, et al. (2018) Decoding the dynamic DNA methylation and hydroxymethylation landscapes in endodermal lineage intermediates during pancreatic differentiation of hESC. Nucleic Acids Res 46: 2883–2900.    
  • 75. Zhang Y, Zhang D, Li Q, et al. (2016) Nucleation of DNA repair factors by FOXA1 links DNA demethylation to transcriptional pioneering. Nat Genet 48: 1003–1013.    
  • 76. Boque-Sastre R, Soler M, Oliveira-Mateos C, et al. (2015) Head-to-head antisense transcription and R-loop formation promotes transcriptional activation. P Natl Acad Sci USA 112: 5785–5790.    


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