TETonic shift: Biological roles of TET proteins in DNA demethylation and transcription

Nature Reviews Molecular Cell Biology

Volumn 14, Issue 6, 2013, Pages 341-356

  Pastor, William A ^a,c   Aravind, L ^b   Rao, Anjana ^a  

^a LA JOLLA INSTITUTE FOR ALLERGY AND IMMUNOLOGY   (United States)

^b NATIONAL INSTITUTES OF HEALTH   (United States)

^c UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

5 METHYLCYTOSINE; AT RICH INTERACTION DOMAIN PROTEIN; DNA METHYLTRANSFERASE 1; DNA METHYLTRANSFERASE 3A; IDAX PROTEIN; KRUPPEL LIKE FACTOR 4; MALATE DEHYDROGENASE 1; OCTAMER TRANSCRIPTION FACTOR 4; OXIDOREDUCTASE; SINGLE STRAND SELECTIVE MONOFUNCTIONAL URACIL DNA GLYCOSYLASE 1; TEN ELEVEN TRANSLOCATION PROTEIN; TEN ELEVEN TRANSLOCATION PROTEIN 1; TEN ELEVEN TRANSLOCATION PROTEIN 2; TEN ELEVEN TRANSLOCATION PROTEIN 3; TRANSCRIPTION FACTOR NANOG; TRANSCRIPTION FACTOR SOX2; UNCLASSIFIED DRUG;

AMINO ACID SEQUENCE; BIOTINYLATION; BRAIN DEVELOPMENT; CARCINOGENESIS; CATALYSIS; CELL DIFFERENTIATION; CPG ISLAND; DECARBOXYLATION; DNA METHYLATION; DNA REPAIR; DNA TRANSCRIPTION; EMBRYO DEVELOPMENT; GEL MOBILITY SHIFT ASSAY; GENE CONTROL; GENE EXPRESSION; GLYCOSYLATION; HEMATOPOIETIC CELL; HUMAN; NEOPLASM; NERVOUS SYSTEM; NONHUMAN; OXIDATION; PRECIPITATION; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN STRUCTURE; REVIEW; XENOPUS LAEVIS;

ANIMALS; CELL DIFFERENTIATION; DNA METHYLATION; DNA-BINDING PROTEINS; EMBRYONIC DEVELOPMENT; HUMANS; NEOPLASMS; PROTO-ONCOGENE PROTEINS;

EID: 84878260646     PISSN: 14710072     EISSN: 14710080     Source Type: Journal    
DOI: 10.1038/nrm3589     Document Type: Review

References (186)

1. Tahiliani, M. et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324, 930-935 (2009).
2. Iyer, L. M., Tahiliani, M., Rao, A. & Aravind, L. Prediction of novel families of enzymes involved in oxidative and other complex modifications of bases in nucleic acids. Cell Cycle 8, 1698-1710 (2009).
3. Ono, R. et al. 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 (2002).
4. Lorsbach, R. B. et al. 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 (2003).
5. Ito, S. et al. Te t proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333, 1300-1303 (2011).
6. He, Y. F. et al. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 333, 1303-1307 (2011).
7. Szwagierczak, A., Bultmann, S., Schmidt, C. S., Spada, F. & Leonhardt, H. Sensitive enzymatic quantification of 5-hydroxymethylcytosine in genomic DNA. Nucleic Acids Res. 38, e181 (2010).
8. Globisch, D. et al. Tissue distribution of 5-hydroxymethylcytosine and search for active demethylation intermediates. PloS one 5, e15367 (2010).
9. Kriaucionis, S. & Heintz, N. The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science 324, 929-930 (2009).
10. Cimmino, L., Abdel-Wahab, O., Levine, R. L. & Aifantis, I. TET family proteins and their role in stem cell differentiation and transformation. Cell Stem Cell 9, 193-204 (2011).
11. Wu, H. & Zhang, Y. Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. Genes Dev. 25, 2436-2452 (2011).
12. Branco, M. R., Ficz, G. & Reik, W. Uncovering the role of 5-hydroxymethylcytosine in the epigenome. Nature Rev. Genet. 13, 7-13 (2012).
13. Williams, K., Christensen, J. & Helin, K. DNA methylation: TET proteins-guardians of CpG islands? EMBO Rep. 13, 28-35 (2012).
14. Tan, L. & Shi, Y. G. Te t family proteins and 5-hydroxymethylcytosine in development and disease. Development 139, 1895-1902 (2012).
15. Bejar, R., Levine, R. & Ebert, B. L. Unraveling the molecular pathophysiology of myelodysplastic syndromes. J. Clin. Oncol. 29, 504-515 (2011).
16. Pronier, E. & Delhommeau, F. Role of TET2 mutations in myeloproliferative neoplasms. Curr. Hematol. Malignancy Rep. 7, 57-64 (2012).
17. Mercher, T. et al. TET2, a tumor suppressor in hematological disorders. Biochim. Biophys. Acta 1825, 173-177 (2012).
18. Iyer, L. M., Anantharaman, V., Wolf, M. Y. & Aravind, L. Comparative genomics of transcription factors and chromatin proteins in parasitic protists and other eukaryotes. Int. J. Parasitol. 38, 1-31 (2008).
19. Gommers-Ampt, J. H. et al. β-d-glucosyl-hydroxymethyluracil: a novel modified base present in the DNA of the parasitic protozoan T. brucei. Cell 75, 1129-1136 (1993).
20. Yu, Z. et al. The protein that binds to DNA base J in trypanosomatids has features of a thymidine hydroxylase. Nucleic Acids Res. 35, 2107-2115 (2007).
21. Loenarz, C. & Schofield, C. J. Expanding chemical biology of 2-oxoglutarate oxygenases. Nature Chem. Biol. 4, 152-156 (2008).
22. Loenarz, C. & Schofield, C. J. Physiological and biochemical aspects of hydroxylations and demethylations catalyzed by human 2-oxoglutarate oxygenases. Trends Biochem. Sci. 36, 7-18 (2011).
23. Aravind, L. & Koonin, E. V. The DNA-repair protein AlkB, EGL-9, and leprecan define new families of 2-oxoglutarate-and iron-dependent dioxygenases. Genome Biol. 2, RESEARCH0007 (2001).
24. Borst, P. & Sabatini, R. Base J: discovery, biosynthesis, and possible functions. Annu. Rev. Microbiol. 62, 235-251 (2008).
25. van Luenen, H. G. et al. Glucosylated hydroxymethyluracil, DNA base j, prevents transcriptional readthrough in leishmania. Cell 150, 909-921 (2012).
26. Ko, M. et al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature 468, 839-843 (2010).
27. Ito, S. et al. Role of Te t proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 466, 1129-1133 (2010).
28. Pfaffeneder, T. et al. The discovery of 5-formylcytosine in embryonic stem cell DNA. Angewandte Chemie 50, 7008-7012 (2011).
29. Penn, N. W., Suwalski, R., O'Riley, C., Bojanowski, K. & Yura, R. The presence of 5-hydroxymethylcytosine in animal deoxyribonucleic acid. Biochem. J. 126, 781-790 (1972).
30. Maiti, A. & Drohat, A. C. 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 (2011).
31. Schiesser, S. et al. Mechanism and stem-cell activity of 5-carboxycytosine decarboxylation determined by isotope tracing. Angewandte Chemie 51, 6516-6520 (2012).
32. Iyer, L. M., Abhiman, S. & Aravind, L. Natural history of eukaryotic DNA methylation systems. Prog. Mol. Biol. Transl. Sci. 101, 25-104 (2011).
33. Frauer, C. et al. Different binding properties and function of CXXC zinc finger domains in Dnmt1 and Tet1. PLoS ONE 6, e16627 (2011).
34. Lee, J. H., Voo, K. S. & Skalnik, D. G. Identification and characterization of the DNA binding domain of CpG-binding protein. J. Biol. Chem. 276, 44669-44676 (2001).
35. Birke, M. et al. The MT domain of the proto-oncoprotein MLL binds to CpG-containing DNA and discriminates against methylation. Nucleic Acids Res. 30, 958-965 (2002).
36. Jorgensen, H. F., Ben-Porath, I. & Bird, A. P. Mbd1 is recruited to both methylated and nonmethylated CpGs via distinct DNA binding domains. Mol. Cell. Biol. 24, 3387-3395 (2004).
37. Blackledge, N. P. et al. CpG islands recruit a histone H3 lysine 36 demethylase. Mol. Cell 38, 179-190 (2010).
38. Allen, M. D. et al. Solution structure of the nonmethyl-CpG-binding CXXC domain of the leukaemia-associated MLL histone methyltransferase. EMBO J. 25, 4503-4512 (2006).
39. Xu, Y. et al. Genome-wide regulation of 5hmC, 5mC, and gene expression by Tet1 hydroxylase in mouse embryonic stem cells. Mol. Cell 42, 451-464 (2011).
40. Zhang, H. et al. TET1 is a DNA-binding protein that modulates DNA methylation and gene transcription via hydroxylation of 5-methylcytosine. Cell Res. 20, 1390-1393 (2010).
41. Ko, M. et al. Modulation of TET2 expression and 5-methylcytosine oxidation by the CXXC domain protein IDAX. Nature 497, 122-126 (2013).
42. Xu, Y. et al. Tet3 CXXC domain and dioxygenase activity cooperatively regulate key genes for Xenopus eye and neural development. Cell 151, 1200-1213 (2012).
43. Hino, S. et al. Inhibition of the Wnt signaling pathway by Idax, a novel Dvl-binding protein. Mol. Cell. Biol. 21, 330-342 (2001).
44. Yu, B. et al. Crystal structures of catalytic complexes of the oxidative DNA/RNA repair enzyme AlkB. Nature 439, 879-884 (2006).
45. Iyer, L. M., Abhiman, S., de Souza, R. F. & Aravind, L. Origin and evolution of peptide-modifying dioxygenases and identification of the wybutosine hydroxylase/hydroperoxidase. Nucleic Acids Res. 38, 5261-5279 (2010).
46. Bird, A. The dinucleotide CG as a genomic signalling module. J. Mol. Biol. 409, 47-53 (2011).
47. Bostick, M. et al. UHRF1 plays a role in maintaining DNA methylation in mammalian cells. Science 317, 1760-1764 (2007).
48. Sharif, J. et al. The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA. Nature 450, 908-912 (2007).
49. Hashimoto, H. et al. Recognition and potential mechanisms for replication and erasure of cytosine hydroxymethylation. Nucleic Acids Res. 40, 4841-4849 (2012).
50. Valinluck, V. & Sowers, L. C. Endogenous cytosine damage products alter the site selectivity of human DNA maintenance methyltransferase DNMT1. Cancer Res. 67, 946-950 (2007).
51. Kubosaki, A. et al. CpG site-specific alteration of hydroxymethylcytosine to methylcytosine beyond DNA replication. Biochem. Biophys. Res. Commun. 426, 141-147 (2012).
52. Guo, J. U., Su, Y., Zhong, C., Ming, G. L. & Song, H. Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell 145, 423-434 (2011).
53. Zhang, L. et al. Thymine DNA glycosylase specifically recognizes 5-carboxylcytosine-modified DNA. Nature Chem. Biol. 8, 328-330 (2012).
54. Nabel, C. S. et al. AID/APOBEC deaminases disfavor modified cytosines implicated in DNA demethylation. Nature Chem. Biol. 8, 751-758 (2012).
55. Song, C. X. et al. Genome-wide profiling of 5-formylcytosine reveals its roles in epigenetic priming. Cell 153, 678-691(2013).
56. Shen, L. et al. Genome-wide analysis reveals TET-and TDG-dependent 5-methylcytosine oxidation dynamics. Cell 153, 692-706 (2013).
57. Rai, K. et al. DNA demethylation in zebrafish involves the coupling of a deaminase, a glycosylase, and gadd45. Cell 135, 1201-1212 (2008).
58. Rai, K. et al. DNA demethylase activity maintains intestinal cells in an undifferentiated state following loss of APC. Cell 142, 930-942 (2010).
59. Popp, C. et al. Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency. Nature 463, 1101-1105 (2010).
60. Bhutani, N. et al. Reprogramming towards pluripotency requires AID-dependent DNA demethylation. Nature 463, 1042-1047 (2010).
61. Cortellino, S. et al. Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair. Cell 146, 67-79 (2011).
62. Cortazar, D. et al. Embryonic lethal phenotype reveals a function of TDG in maintaining epigenetic stability. Nature 470, 419-423 (2011).
63. Bransteitter, R., Pham, P., Scharff, M. D. & Goodman, M. F. Activation-induced cytidine deaminase deaminates deoxycytidine on single-stranded DNA but requires the action of RNase. Proc. Natl Acad. Sci. USA 100, 4102-4107 (2003).
64. Rangam, G., Schmitz, K. M., Cobb, A. J. & Petersen-Mahrt, S. K. AID enzymatic activity is inversely proportional to the size of cytosine C5 orbital cloud. PloS one 7, e43279 (2012).
65. Liutkeviciute, Z., Lukinavicius, G., Masevicius, V., Daujotyte, D. & Klimasauskas, S. Cytosine-5-methyltransferases add aldehydes to DNA. Nature Chem. Biol. 5, 400-402 (2009).
66. Chen, C. C., Wang, K. Y. & Shen, C. K. The mammalian de novo DNA.methyltransferases, DNMT3A and DNMT3B are also DNA 5-hydroxymethylcytosine dehydroxymethylases. J. Biol. Chem. 287, 33116-33121 (2012).
67. Metivier, R. et al. Cyclical DNA methylation of a transcriptionally active promoter. Nature 452, 45-50 (2008).
68. Kangaspeska, S. et al. Transient cyclical methylation of promoter DNA. Nature 452, 112-115 (2008).
69. Hsieh, C. L. Evidence that protein binding specifies sites of DNA demethylation. Mol. Cell. Biol. 19, 46-56 (1999).
70. Lin, I. G., Tomzynski, T. J., Ou, Q. & Hsieh, C. L. Modulation of DNA binding protein affinity directly affects target site demethylation. Mol. Cell. Biol. 20, 2343-2349 (2000).
71. Brandeis, M. et al. Sp1 elements protect a CpG island from de novo methylation. Nature 371, 435-438 (1994).
72. Stadler, M. B. et al. DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature 480, 490-495 (2011).
73. Szulwach, K. E. et al. Integrating 5-Hydroxymethylcytosine into the epigenomic landscape of human embryonic stem cells. PLoS Genet. 7, e1002154 (2011).
74. Wu, H. & Zhang, Y. Tet1 and 5-hydroxymethylation: a genome-wide view in mouse embryonic stem cells. Cell Cycle 10, 2428-2436 (2011).
75. Stroud, H., Feng, S., Morey Kinney, S., Pradhan, S. & Jacobsen, S. E. 5-hydroxymethylcytosine is associated with enhancers and gene bodies in human embryonic stem cells. Genome Biol. 12, R54 (2011).
76. Pastor, W. A. et al. Genome-wide mapping of 5-hydroxymethylcytosine in embryonic stem cells. Nature 473, 394-397 (2011).
77. Hahn, M. A. et al. Dynamics of 5-hydroxymethylcytosine and chromatin marks in mammalian neurogenesis. Cell Rep. 3, 291-300 (2013).
78. Szulwach, K. E. et al. 5-hmC-mediated epigenetic dynamics during postnatal neurodevelopment and aging. Nature Neurosci. 14, 1607-1616 (2011).
79. Weber, M. et al. Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nature Genet. 39, 457-466 (2007).
80. Hackett, J. A. et al. Germline DNA demethylation dynamics and imprint erasure through 5-hydroxymethylcytosine. Science 339, 448-452 (2013).
81. Thomson, J. P. et al. Non-genotoxic carcinogen exposure induces defined changes in the 5-hydroxymethylome. Genome Biol. 13, R93 (2012).
82. Lian, C. G. et al. Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma. Cell 150, 1135-1146 (2012).
83. Raiber, E. A. et al. Genome-wide distribution of 5-formylcytosine in ES cells is associated with transcription and depends on thymine DNA glycosylase. Genome Biol. 13, R69 (2012).
84. Wu, H. et al. Genome-wide analysis of 5-hydroxymethylcytosine distribution reveals its dual function in transcriptional regulation in mouse embryonic stem cells. Genes Dev. 25, 679-684 (2011).
85. 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 151, 1417-1430 (2012).
86. Lister, R. et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462, 315-322 (2009).
87. Straussman, R. et al. Developmental programming of CpG island methylation profiles in the human genome. Nature Struct. Mol. Biol. 16, 564-571 (2009).
88. Weber, M. et al. Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells. Nature Genet. 37, 853-862 (2005).
89. Yu, M. et al. Base-resolution analysis of 5-hydroxymethylcytosine in the mammalian genome. Cell 149, 1368-1380 (2012).
90. Hsieh, C. L. Dependence of transcriptional repression on CpG methylation density. Mol. Cell. Biol. 14, 5487-5494 (1994).
91. Serandour, A. A. et al. Dynamic hydroxymethylation of deoxyribonucleic acid marks differentiation-associated enhancers. Nucleic Acids Res. 40, 8255-8265 (2012).
92. Wu, H. et al. Dual functions of Tet1 in transcriptional regulation in mouse embryonic stem cells. Nature 473, 389-393 (2011).
93. Williams, K. et al. TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity. Nature 473, 343-348 (2011).
94. Deplus, R. et al. TET2 and TET3 regulate GlcNAcylation and H3K4 methylation through OGT and SET1/COMPASS. EMBO J. 32, 645-655 (2013).
95. Chen, Q., Chen, Y., Bian, C., Fujiki, R. & Yu, X. TET2 promotes histone O-GlcNAcylation during gene transcription. Nature 493, 561-564 (2013).
96. Yildirim, O. et al. Mbd3/NURD complex regulates expression of 5-hydroxymethylcytosine marked genes in embryonic stem cells. Cell 147, 1498-1510 (2011).
97. Vella, P. et al. Tet proteins connect the O-linked N-acetylglucosamine transferase Ogt to chromatin in embryonic stem cells. Mol. Cell 49, 645-656 (2013).
98. Jackson-Grusby, L. et al. Loss of genomic methylation causes p53-dependent apoptosis and epigenetic deregulation. Nature Genet. 27, 31-39 (2001).
99. Fouse, S. D. et al. Promoter CpG methylation contributes to ES cell gene regulation in parallel with Oct4/Nanog, PcG complex, and histone H3 K4/K27 trimethylation. Cell Stem Cell 2, 160-169 (2008).
100. Balasubramani, A. & Rao, A. O-GlcNAcylation and 5-methylcytosine oxidation: an unexpected association between OGT and TETs. Mol. Cell 49, 618-619 (2013).
101. Hart, G. W., Slawson, C., Ramirez-Correa, G. & Lagerlof, O. Cross talk between O-GlcNAcylation and phosphorylation: roles in signaling, transcription, and chronic disease. Annu. Rev. Biochem. 80, 825-858 (2011).
102. Fujiki, R. et al. GlcNAcylation of histone H2B facilitates its monoubiquitination. Nature 480, 557-560 (2011).
103. Mayer, W., Niveleau, A., Walter, J., Fundele, R. & Haaf, T. Demethylation of the zygotic paternal genome. Nature 403, 501-502 (2000).
104. Oswald, J. et al. Active demethylation of the paternal genome in the mouse zygote. Curr. Biol. 10, 475-478 (2000).
105. Santos, F., Hendrich, B., Reik, W. & Dean, W. Dynamic reprogramming of DNA methylation in the early mouse embryo. Dev. Biol. 241, 172-182 (2002).
106. Huang, Y. et al. The behaviour of 5-hydroxymethylcytosine in bisulfite sequencing. PLoS ONE 5, e8888 (2010).
107. Nestor, C., Ruzov, A., Meehan, R. & Dunican, D. Enzymatic approaches and bisulfite sequencing cannot distinguish between 5-methylcytosine and 5-hydroxymethylcytosine in DNA. Biotechniques 48, 317-319 (2010).
108. Jin, S. G., Kadam, S. & Pfeifer, G. P. Examination of the specificity of DNA methylation profiling techniques towards 5-methylcytosine and 5-hydroxymethylcytosine. Nucleic Acids Res. 38, e125 (2010).
109. Okada, Y., Yamagata, K., Hong, K., Wakayama, T. & Zhang, Y. A role for the elongator complex in zygotic paternal genome demethylation. Nature 463, 554-558 (2010).
110. Wossidlo, M. et al. Dynamic link of DNA demethylation, DNA strand breaks and repair in mouse zygotes. EMBO J. 29, 1877-1888 (2010).
111. Iqbal, K., Jin, S. G., Pfeifer, G. P. & Szabo, P. E. Reprogramming of the paternal genome upon fertilization involves genome-wide oxidation of 5-methylcytosine. Proc. Natl Acad. Sci. USA 108, 3642-3647 (2011).
112. Wossidlo, M. et al. 5-Hydroxymethylcytosine in the mammalian zygote is linked with epigenetic reprogramming. Nature Commun. 2, 241 (2011).
113. Gu, T. P. et al. The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes. Nature 477, 606-610 (2011).
114. Inoue, A., Shen, L., Dai, Q., He, C. & Zhang, Y. Generation and replication-dependent dilution of 5fC and 5caC during mouse preimplantation development. Cell Res. 21, 1670-1676 (2011).
115. Nakamura, T. et al. PGC7 binds histone H3K9me2 to protect against conversion of 5mC to 5hmC in early embryos. Nature 486, 415-419 (2012).
116. Nakamura, T. et al. PGC7/Stella protects against DNA demethylation in early embryogenesis. Nature Cell Biol. 9, 64-71 (2007).
117. Bortvin, A., Goodheart, M., Liao, M. & Page, D. C. Dppa3/Pgc7/stella is a maternal factor and is not required for germ cell specification in mice. BMC Dev. Biol. 4, 2 (2004).
118. Payer, B. et al. Stella is a maternal effect gene required for normal early development in mice. Curr. Biol. 13, 2110-2117 (2003).
119. Inoue, A. & Zhang, Y. Replication-dependent loss of 5-hydoxymethylcytosine in mouse preimplantation embryos. Science 334, 194 (2011).
120. Hajkova, P. et al. Genome-wide reprogramming in the mouse germ line entails the base excision repair pathway. Science 329, 78-82 (2010).
121. Aoki, F., Worrad, D. M. & Schultz, R. M. Regulation of transcriptional activity during the first and second cell cycles in the preimplantation mouse embryo. Dev. Biol. 181, 296-307 (1997).
122. Inoue, A., Matoba, S. & Zhang, Y. Transcriptional activation of transposable elements in mouse zygotes is independent of Tet3-mediated 5-methylcytosine oxidation. Cell Res. 22, 1640-1649 (2012).
123. Dawlaty, M. M. et al. Tet1 is dispensable for maintaining pluripotency and its loss is compatible with embryonic and postnatal development. Cell Stem Cell 9, 166-175 (2011).
124. Dawlaty, M. M. et al. Combined deficiency of Tet1 and Tet2 causes epigenetic abnormalities but is compatible with postnatal development. Dev. Cell 24, 310-323 (2013).
125. Koh, K. P. et al. Tet1 and Tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells. Cell Stem Cell 8, 200-213 (2011).
126. Ficz, G. et al. Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation. Nature 473, 398-402 (2011).
127. Vincent, J. J. et al. Stage-specific roles for Tet1 and Tet2 in DNA demethylation in primordial germ cells. Cell stem cell 12, 470-478 (2013).
128. Hackett, J. A., Zylicz, J. J. & Surani, M. A. Parallel mechanisms of epigenetic reprogramming in the germline. Trends Genet. 28, 164-174 (2012).
129. Yamaguchi, S. et al. Tet1 controls meiosis by regulating meiotic gene expression. Nature 492, 443-447 (2012).
130. Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663-676 (2006).
131. Cox, J. L. & Rizzino, A. Induced pluripotent stem cells: what lies beyond the paradigm shift. Exp. Biol. Med. 235, 148-158 (2010).
132. Mikkelsen, T. S. et al. Dissecting direct reprogramming through integrative genomic analysis. Nature 454, 49-55 (2008).
133. Doege, C. A. et al. Early-stage epigenetic modification during somatic cell reprogramming by Parp1 and Tet2. Nature 488, 652-655 (2012).
134. Costa, Y. et al. NANOG-dependent function of TET1 and TET2 in establishment of pluripotency. Nature 495, 370-374 (2013).
135. Gao, Y. et al. Replacement of Oct4 by Tet1 during iPSC induction reveals an important role of DNA methylation and hydroxymethylation in reprogramming. Cell Stem Cell 12, 453-469 (2013).
136. Spruijt, C. G. et al. Dynamic readers for 5-(hydroxy) methylcytosine and its oxidized derivatives. Cell 152, 1146-1159 (2013).
137. Otani, J. et al. Structural basis of the versatile DNA recognition ability of the methyl-CpG binding domain of methyl-CpG binding domain protein 4. J. Biol. Chem. 288, 6351-6362 (2013).
138. Tini, M. et al. Association of CBP/p300 acetylase and thymine DNA glycosylase links DNA repair and transcription. Mol. Cell 9, 265-277 (2002).
139. Cortazar, D., Kunz, C., Saito, Y., Steinacher, R. & Schar, P. The enigmatic thymine DNA glycosylase. DNA Repair 6, 489-504 (2007).
140. Kellinger, M. W. et al. 5-formylcytosine and 5-carboxylcytosine reduce the rate and substrate specificity of RNA polymerase II transcription. Nature Struct. Mol. Biol. 19, 831-833 (2012).
141. Jin, S. G., Wu, X., Li, A. X. & Pfeifer, G. P. Genomic mapping of 5-hydroxymethylcytosine in the human brain. Nucleic Acids Res. 39, 5015-5024 (2011).
142. Matarese, F., Carrillo-de Santa Pau, E. & Stunnenberg, H. G. 5-Hydroxymethylcytosine: a new kid on the epigenetic block? Mol. Systems Biol. 7, 562 (2011).
143. Hayatsu, H. & Shiragami, M. Reaction of bisulfite with the 5-hydroxymethyl group in pyrimidines and in phage DNAs. Biochemistry 18, 632-637 (1979).
144. Huang, Y., Pastor, W. A., Zepeda-Martinez, J. A. & Rao, A. The anti-CMS technique for genome-wide mapping of 5-hydroxymethylcytosine. Nature Protoc. 7, 1897-1908 (2012).
145. Pastor, W. A., Huang, Y., Henderson, H. R., Agarwal, S. & Rao, A. The GLIB technique for genome-wide mapping of 5-hydroxymethylcytosine. Nature Protoc. 7, 1909-1917 (2012).
146. Robertson, A. B. et al. A novel method for the efficient and selective identification of 5-hydroxymethylcytosine in genomic DNA. Nucleic Acids Res. 39, e55 (2011).
147. Song, C. X. et al. Selective chemical labeling reveals the genome-wide distribution of 5-hydroxymethylcytosine. Nature Biotechnol. 29, 68-72 (2011).
148. Zilberman, D. & Henikoff, S. Genome-wide analysis of DNA methylation patterns. Development 134, 3959-3965 (2007).
149. Krueger, F., Kreck, B., Franke, A. & Andrews, S. R. DNA methylome analysis using short bisulfite sequencing data. Nature Methods 9, 145-151 (2012).
150. Rein, T., DePamphilis, M. L. & Zorbas, H. Identifying 5-methylcytosine and related modifications in DNA genomes. Nucleic Acids Res. 26, 2255-2264 (1998).
151. Booth, M. J. et al. Quantitative sequencing of 5-methylcytosine and 5-hydroxymethylcytosine at single-base resolution. Science 336, 934-937 (2012).
152. Song, C. X. et al. Sensitive and specific single-molecule sequencing of 5-hydroxymethylcytosine. Nature Methods 9, 75-77 (2012).
153. Clark, T. A. et al. Enhanced 5-methylcytosine detection in single-molecule, real-time sequencing via Tet1 oxidation. BMC Biol. 11, 4 (2013).
154. Quivoron, C. et al. TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis. Cancer Cell 20, 25-38 (2011).
155. Moran-Crusio, K. et al. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell 20, 11-24 (2011).
156. Ko, M. et al. Ten-eleven-translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice. Proc. Natl Acad. Sci. USA 108, 14566-14571 (2011).
157. Li, Z. et al. Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies. Blood 118, 4509-4518 (2011).
158. Shide, K. et al. TET2 is essential for survival and hematopoietic stem cell homeostasis. Leukemia 26, 2216-2223 (2012).
159. Ng, H. H. et al. MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex. Nature Genet. 23, 58-61 (1999).
160. Kass, S. U., Landsberger, N. & Wolffe, A. P. DNA methylation directs a time-dependent repression of transcription initiation. Curr. Biol. 7, 157-165 (1997).
161. Ng, H. H., Jeppesen, P. & Bird, A. Active repression of methylated genes by the chromosomal protein MBD1. Mol. Cell. Biol. 20, 1394-1406 (2000).
162. Fujita, N. et al. MCAF mediates MBD1-dependent transcriptional repression. Mol. Cell. Biol. 23, 2834-2843 (2003).
163. Sarraf, S. A. & Stancheva, I. Methyl-CpG binding protein MBD1 couples histone H3 methylation at lysine 9 by SETDB1 to DNA replication and chromatin assembly. Mol. Cell 15, 595-605 (2004).
164. Prokhortchouk, A. et al. The p120 catenin partner Kaiso is a DNA methylation-dependent transcriptional repressor. Genes Dev. 15, 1613-1618 (2001).
165. Valinluck, V. et al. Oxidative damage to methyl-CpG sequences inhibits the binding of the methyl-CpG binding domain (MBD) of methyl-CpG binding protein 2 (MeCP2). Nucleic Acids Res. 32, 4100-4108 (2004).
166. Prokhortchouk, A. et al. Kaiso-deficient mice show resistance to intestinal cancer. Mol. Cell. Biol. 26, 199-208 (2006).
167. Zhao, X. et al. Mice lacking methyl-CpG binding protein 1 have deficits in adult neurogenesis and hippocampal function. Proc. Natl Acad. Sci. USA 100, 6777-6782 (2003).
168. Hendrich, B., Guy, J., Ramsahoye, B., Wilson, V. A. & Bird, A. Closely related proteins MBD2 and MBD3 play distinctive but interacting roles in mouse development. Genes Dev. 15, 710-723 (2001).
169. Jones, P. L. et al. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nature Genet. 19, 187-191 (1998).
170. Ben-Shachar, S., Chahrour, M., Thaller, C., Shaw, C. A. & Zoghbi, H. Y. Mouse models of MeCP2 disorders share gene expression changes in the cerebellum and hypothalamus. Hum. Mol. Genet. 18, 2431-2442 (2009).
171. Skene, P. J. et al. Neuronal MeCP2 is expressed at near histone-octamer levels and globally alters the chromatin state. Mol. Cell 37, 457-468 (2010).
172. Klose, R. J. & Bird, A. P. Genomic DNA methylation: the mark and its mediators. Trends Biochem. Sci. 31, 89-97 (2006).
173. Lee, J. H. & Skalnik, D. G. CpG-binding protein (CXXC finger protein 1) is a component of the mammalian Set1 histone H3-Lys4 methyltransferase complex, the analogue of the yeast Set1/COMPASS complex. J. Biol. Chem. 280, 41725-41731 (2005).
174. Choy, J. S. et al. DNA methylation increases nucleosome compaction and rigidity. J. Am. Chem. Soc. 132, 1782-1783 (2010).
175. Watt, F. & Molloy, P. L. Cytosine methylation prevents binding to DNA of a HeLa cell transcription factor required for optimal expression of the adenovirus major late promoter. Genes Dev. 2, 1136-1143 (1988).
176. Zheng, Y. et al. Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature 463, 808-812 (2010).
177. Bell, A. C. & Felsenfeld, G. Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene. Nature 405, 482-485 (2000).
178. Miranda, T. B. & Jones, P. A. DNA methylation: the nuts and bolts of repression. J. Cell. Physiol. 213, 384-390 (2007).
179. Wu, H. et al. Dnmt3a-dependent nonpromoter DNA methylation facilitates transcription of neurogenic genes. Science 329, 444-448 (2010).
180. Brinkman, A. B. et al. Sequential ChIP-bisulfite sequencing enables direct genome-scale investigation of chromatin and DNA methylation cross-talk. Genome Res. 22, 1128-1138 (2012).
181. Acosta-Silva, C., Branchadell, V., Bertran, J. & Oliva, A. Mutual relationship between stacking and hydrogen bonding in DNA. Theoretical study of guanine-cytosine, guanine-5-methylcytosine, and their dimers. J. Phys. Chem. B 114, 10217-10227 (2010).
182. Thalhammer, A., Hansen, A. S., El-Sagheer, A. H., Brown, T. & Schofield, C. J. Hydroxylation of methylated CpG dinucleotides reverses stabilisation of DNA duplexes by cytosine 5-methylation. Chem. Commun. (Camb.) 47, 5325-5327 (2011).
183. Borgel, J. et al. Targets and dynamics of promoter DNA methylation during early mouse development. Nature Genet. 42, 1093-1100 (2010).
184. Lane, N. et al. Resistance of IAPs to methylation reprogramming may provide a mechanism for epigenetic inheritance in the mouse. Genesis 35, 88-93 (2003).
185. + human primordial germ cells proves to be a resource for human germ line reprogramming, imprint erasure and in vitro differentiation. Nature Cell Biol. 15, 113-122 (2013).
186. Reik, W., Dean, W. & Walter, J. Epigenetic reprogramming in mammalian development. Science 293, 1089-1093 (2001).