Modifiers and readers of DNA modifications and their impact on genome structure, expression, and stability in disease

Frontiers in Genetics

Volumn 7, Issue JUN, 2016, Pages

  Ludwig, Anne K ^a   Zhang, Peng ^a   Cardoso, M C ^a  

^a DARMSTADT UNIVERSITY OF TECHNOLOGY   (Germany)

Author keywords

Cytosine modifications; Dnmt; Epigenetics; Hydroxymethylcytosine; MBD; Methylcytosine; Mouse models; Tet

Indexed keywords

5 HYDROXYMETHYLCYTOSINE; 5 METHYLCYTOSINE; CYTOSINE; DNA METHYLTRANSFERASE; KAISO PROTEIN; MBD1 PROTEIN; MBD3 PROTEIN; MBD4 PROTEIN; MECP 2 PROTEIN; METHYL CPG BINDING PROTEIN 2; PEPTIDES AND PROTEINS; RNA METHYLTRANSFERASE; TET PROTEIN; UNCLASSIFIED DRUG;

DNA METHYLATION; DNA MODIFICATION; DNA REPLICATION; DNMT1 GENE; EMBRYO DEVELOPMENT; GENE; GENE EXPRESSION; GENE MUTATION; GENE STRUCTURE; GENETIC STABILITY; LEUKEMIA; MYELOPROLIFERATIVE NEOPLASM; NONHUMAN; REVIEW;

EID: 84977526612     PISSN: None     EISSN: 16648021     Source Type: Journal    
DOI: 10.3389/fgene.2016.00115     Document Type: Review

References (291)

1. Aapola, U., Kawasaki, K., Scott, H. S., Ollila, J., Vihinen, M., Heino, M., et al. (2000). Isolation and initial characterization of a novel zinc finger gene, DNMT3L, on 21q22.3, related to the cytosine-5-methyltransferase 3 gene family. Genomics 65, 293-298. doi: 10.1006/geno.2000.6168
2. Abdel-Wahab, O., Mullally, A., Hedvat, C., Garcia-Manero, G., Patel, J., Wadleigh, M., et al. (2009). Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood 114, 144-147. doi: 10.1182/blood-2009-03-210039
3. Achour, M., Fuhrmann, G., Alhosin, M., Ronde, P., Chataigneau, T., Mousli, M., et al. (2009). UHRF1 recruits the histone acetyltransferase Tip60 and controls its expression and activity. Biochem. Biophys. Res. Commun. 390, 523-528. doi: 10.1016/j.bbrc.2009.09.131
4. Adams, V. H., McBryant, S. J., Wade, P. A., Woodcock, C. L., and Hansen, J. C. (2007). Intrinsic disorder and autonomous domain function in the multifunctional nuclear protein, MeCP2. J. Biol. Chem. 282, 15057-15064. doi: 10.1074/jbc. M700855200
5. Agarwal, N., Becker, A., Jost, K. L., Haase, S., Thakur, B. K., Brero, A., et al. (2011). MeCP2 Rett mutations affect large scale chromatin organization. Hum. Mol. Genet. 20, 4187-4195. doi: 10.1093/hmg/ddr346
6. Ahluwalia, A., Hurteau, J. A., Bigsby, R. M., and Nephew, K. P. (2001). DNA methylation in ovarian cancer. II. Expression of DNA methyltransferases in ovarian cancer cell lines and normal ovarian epithelial cells. Gynecol. Oncol. 82, 299-304. doi: 10.1006/gyno.2001.6284
7. Akbarian, S., Chen, R. Z., Gribnau, J., Rasmussen, T. P., Fong, H., Jaenisch, R., et al. (2001). Expression pattern of the Rett syndrome gene MeCP2 in primate prefrontal cortex. Neurobiol. Dis. 8, 784-791. doi: 10.1006/nbdi.2001.0420
8. Amir, R. E., Van den Veyver, I. B., Wan, M., Tran, C. Q., Francke, U., and Zoghbi, H. Y. (1999). Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat. Genet. 23, 185-188. doi: 10.1038/13810
9. Amouroux, R., Nashun, B., Shirane, K., Nakagawa, S., Hill, P. W. S., D'Souza, Z., et al. (2016). De novo DNA methylation drives 5hmC accumulation in mouse zygotes. Nat. Cell Biol. 18, 225-233. doi: 10.1038/ncb3296
10. Aoki, A., Suetake, I., Miyagawa, J., Fujio, T., Chijiwa, T., Sasaki, H., et al. (2001). Enzymatic properties of de novo-type mouse DNA (cytosine-5) methyltransferases. Nucleic Acids Res. 29, 3506-3512. doi: 10.1093/nar/29.17.3506
11. Arita, K., Ariyoshi, M., Tochio, H., Nakamura, Y., and Shirakawa, M. (2008). Recognition of hemi-methylated DNA by the SRA protein UHRF1 by a base-flipping mechanism. Nature 455, 818-821. doi: 10.1038/nature07249
12. Arita, K., Isogai, S., Oda, T., Unoki, M., Sugita, K., Sekiyama, N., et al. (2012). Recognition of modification status on a histone H3 tail by linked histone reader modules of the epigenetic regulator UHRF1. Proc. Natl. Acad. Sci. U.S.A. 109, 12950-12955. doi: 10.1073/pnas.1203701109
13. Avvakumov, G. V., Walker, J. R., Xue, S., Li, Y., Duan, S., Bronner, C., et al. (2008). Structural basis for recognition of hemi-methylated DNA by the SRA domain of human UHRF1. Nature 455, 822-825. doi: 10.1038/nature07273
14. Bachman, M., Uribe-Lewis, S., Yang, X., Williams, M., Murrell, A., and Balasubramanian, S. (2014). 5-Hydroxymethylcytosine is a predominantly stable DNA modification. Nat. Chem. 6, 1049-1055. doi: 10.1038/nchem.2064
15. Bader, S., Walker, M., Hendrich, B., Bird, A., Bird, C., Hooper, M., et al. (1999). Somatic frameshift mutations in the MBD4 gene of sporadic colon cancers with mismatch repair deficiency. Oncogene 18, 8044-8047. doi: 10.1038/sj.onc.1203229
16. Ballestar, E., Yusufzai, T. M., and Wolffe, A. P. (2000). Effects of Rett syndrome mutations of the methyl-CpG binding domain of the transcriptional repressor MeCP2 on selectivity for association with methylated DNA. Biochemistry 39, 7100-7106. doi: 10.1021/bi0001271
17. Baubec, T., Ivanek, R., Lienert, F., and Schubeler, D. (2013). Methylation-dependent and-independent genomic targeting principles of the MBD protein family. Cell 153, 480-492. doi: 10.1016/j.cell.2013.03.011
18. Bauer, C., Göbel, K., Nagaraj, N., Colantuoni, C., Wang, M., Müller, U., et al. (2015). Phosphorylation of TET proteins is regulated via O-GlcNAcylation by the O-Linked N-Acetylglucosamine transferase (OGT). J. Biol. Chem. 290, 4801-4812. doi: 10.1074/jbc. M114.605881
19. Baymaz, H. I., Fournier, A., Laget, S., Ji, Z., Jansen, P. W., Smits, A. H., et al. (2014). MBD5 and MBD6 interact with the human PR-DUB complex through their methyl-CpG-binding domain. Proteomics 14, 2179-2189. doi: 10.1002/pmic.201400013
20. Becker, A., Allmann, L., Hofstatter, M., Casa, V., Weber, P., Lehmkuhl, A., et al. (2013). Direct homo-and hetero-interactions of MeCP2 and MBD2. PLoS ONE 8:e53730. doi: 10.1371/journal.pone.0053730
21. Becker, A., Zhang, P., Allmann, L., Meilinger, D., Bertulat, B., Eck, D., et al. (2016). Poly(ADP-ribosyl)ation of Methyl CpG Binding Domain Protein 2 regulates chromatin structure. J. Biol. Chem. 291, 4873-4881. doi: 10.1074/jbc. M115.698357
22. Bednar, J., Horowitz, R. A., Grigoryev, S. A., Carruthers, L. M., Hansen, J. C., Koster, A. J., et al. (1998). Nucleosomes, linker DNA, and linker histone form a unique structural motif that directs the higher-order folding and compaction of chromatin. Proc. Natl. Acad. Sci. U.S.A. 95, 14173-14178. doi: 10.1073/pnas.95.24.14173
23. Bellacosa, A., Cicchillitti, L., Schepis, F., Riccio, A., Yeung, A. T., Matsumoto, Y., et al. (1999). MED1, a novel human methyl-CpG-binding endonuclease, interacts with DNA mismatch repair protein MLH1. Proc. Natl. Acad. Sci. U.S.A. 96, 3969-3974. doi: 10.1073/pnas.96.7.3969
24. Bestor, T., Laudano, A., Mattaliano, R., and Ingram, V. (1988). Cloning and sequencing of a cDNA encoding DNA methyltransferase of mouse cells. J. Mol. Biol. 203, 971-983. doi: 10.1016/0022-2836(88)90122-2
25. Bhattacharya, S. K., Ramchandani, S., Cervoni, N., and Szyf, M. (1999). A mammalian protein with specific demethylase activity for mCpG DNA. Nature 397, 579-583. doi: 10.1038/17533
26. Bian, C., and Yu, X. (2014). PGC7 suppresses TET3 for protecting DNA methylation. Nucleic Acids Res. 42, 2893-2905. doi: 10.1093/nar/gkt1261
27. Billard, L. M., Magdinier, F., Lenoir, G. M., Frappart, L., and Dante, R. (2002). MeCP2 and MBD2 expression during normal and pathological growth of the human mammary gland. Oncogene 21, 2704-2712. doi: 10.1038/sj/onc/1205357
28. Birke, M., Schreiner, S., Garcia-Cuellar, M. P., Mahr, K., Titgemeyer, F., and Slany, R. K. (2002). The MT domain of the proto-oncoprotein MLL binds to CpG-containing DNA and discriminates against methylation. Nucleic Acids Res. 30, 958-965. doi: 10.1093/nar/30.4.958
29. Blaschke, K., Ebata, K. T., Karimi, M. M., Zepeda-Martinez, J. A., Goyal, P., Mahapatra, S., et al. (2013). Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. Nature 500, 222-226. doi: 10.1038/nature12362
30. Boeke, J., Ammerpohl, O., Kegel, S., Moehren, U., and Renkawitz, R. (2000). The minimal repression domain of MBD2b overlaps with the methyl-CpG-binding domain and binds directly to Sin3A. J. Biol. Chem. 275, 34963-34967. doi: 10.1074/jbc. M005929200
31. Bostick, M., Kim, J. K., Esteve, P. O., Clark, A., Pradhan, S., and Jacobsen, S. E. (2007). UHRF1 plays a role in maintaining DNA methylation in mammalian cells. Science 317, 1760-1764. doi: 10.1126/science.1147939
32. Bourc'his, D., Xu, G. L., Lin, C. S., Bollman, B., and Bestor, T. H. (2001). Dnmt3L and the establishment of maternal genomic imprints. Science (New York) 294, 2536-2539. doi: 10.1126/science.1065848
33. Bradley-Whitman, M. A., and Lovell, M. A. (2013). Epigenetic changes in the progression of Alzheimer's disease. Mech. Ageing Dev. 134, 486-495. doi: 10.1016/j.mad.2013.08.005
34. Brero, A., Easwaran, H. P., Nowak, D., Grunewald, I., Cremer, T., Leonhardt, H., et al. (2005). Methyl CpG-binding proteins induce large-scale chromatin reorganization during terminal differentiation. J. Cell Biol. 169, 733-743. doi: 10.1083/jcb.20002062
35. Cardoso, M. C., and Leonhardt, H. (1999). DNA methyltransferase is actively retained in the cytoplasm during early development. J. Cell Biol. 147, 25-32. doi: 10.1083/jcb.147.1.25
36. Carney, R. M., Wolpert, C. M., Ravan, S. A., Shahbazian, M., Ashley-Koch, A., Cuccaro, M. L., et al. (2003). Identification of MeCP2 mutations in a series of females with autistic disorder. Pediatr. Neurol. 28, 205-211. doi: 10.1016/S0887-8994(02)00624-0
37. Casas-Delucchi, C. S., Becker, A., Bolius, J. J., and Cardoso, M. C. (2012). Targeted manipulation of heterochromatin rescues MeCP2 Rett mutants and re-establishes higher order chromatin organization. Nucleic Acids Res. 40, e176. doi: 10.1093/nar/gks784
38. Chahrour, M., Jung, S. Y., Shaw, C., Zhou, X., Wong, S. T., Qin, J., et al. (2008). MeCP2, a key contributor to neurological disease, activates and represses transcription. Science 320, 1224-1229. doi: 10.1126/science.1153252
39. Chen, Q., Chen, Y., Bian, C., Fujiki, R., and Yu, X. (2013). TET2 promotes histone O-GlcNAcylation during gene transcription. Nature 493, 561-564. doi: 10.1038/nature11742
40. Chen, R. Z., Akbarian, S., Tudor, M., and Jaenisch, R. (2001). Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. Nat. Genet. 27, 327-331. doi: 10.1038/85906
41. Chen, T., Ueda, Y., Dodge, J. E., Wang, Z., and Li, E. (2003). Establishment and maintenance of genomic methylation patterns in mouse embryonic stem cells by Dnmt3a and Dnmt3b. Mol. Cell. Biol. 23, 5594-5605. doi: 10.1128/MCB.23.16.5594
42. Chen, T., Ueda, Y., Xie, S., and Li, E. (2002). A novel Dnmt3a isoform produced from an alternative promoter localizes to euchromatin and its expression correlates with active de novo methylation. J. Biol. Chem. 277, 38746-38754. doi: 10.1074/jbc. M205312200
43. Cheng, J., Huang, M., Zhu, Y., Xin, Y. J., Zhao, Y. K., Huang, J., et al. (2014). SUMOylation of MeCP2 is essential for transcriptional repression and hippocampal synapse development. J. Neurochem. 128, 798-806. doi: 10.1111/jnc.12523
44. Cheng, J., Yang, Y., Fang, J., Xiao, J., Zhu, T., Chen, F., et al. (2013). Structural insight into coordinated recognition of trimethylated histone H3 lysine 9 (H3K9me3) by the plant homeodomain (PHD) and tandem tudor domain (TTD) of UHRF1 (ubiquitin-like, containing PHD and RING finger domains, 1) protein. J. Biol. Chem. 288, 1329-1339. doi: 10.1074/jbc. M112.415398
45. Christodoulou, J., Grimm, A., Maher, T., and Bennetts, B. (2003). RettBASE: the IRSA MECP2 variation database-a new mutation database in evolution. Hum. Mutat. 21, 466-472. doi: 10.1002/humu.10194
46. Cohen, S., Gabel, H. W., Hemberg, M., Hutchinson, A. N., Sadacca, L. A., Ebert, D. H., et al. (2011). Genome-wide activity-dependent MeCP2 phosphorylation regulates nervous system development and function. Neuron 72, 72-85. doi: 10.1016/j.neuron.2011.08.022
47. Costa, Y., Ding, J., Theunissen, T. W., Faiola, F., Hore, T. A., Shliaha, P. V., et al. (2013). NANOG-dependent function of TET1 and TET2 in establishment of pluripotency. Nature 495, 370-374. doi: 10.1038/nature11925
48. Cross, S. H., Meehan, R. R., Nan, X., and Bird, A. (1997). A component of the transcriptional repressor MeCP1 shares a motif with DNA methyltransferase and HRX proteins. Nat. Genet. 16, 256-259. doi: 10.1038/ng0797-256
49. Daniel, J. M., and Reynolds, A. B. (1999). The catenin p120(ctn) interacts with Kaiso, a novel BTB/POZ domain zinc finger transcription factor. Mol. Cell. Biol. 19, 3614-3623. doi: 10.1128/MCB.19.5.3614
50. Daniel, J. M., Spring, C. M., Crawford, H. C., Reynolds, A. B., and Baig, A. (2002). The p120(ctn)-binding partner Kaiso is a bi-modal DNA-binding protein that recognizes both a sequence-specific consensus and methylated CpG dinucleotides. Nucleic Acids Res. 30, 2911-2919. doi: 10.1093/nar/gkf398
51. Daskalos, A., Oleksiewicz, U., Filia, A., Nikolaidis, G., Xinarianos, G., Gosney, J. R., et al. (2011). UHRF1-mediated tumor suppressor gene inactivation in nonsmall cell lung cancer. Cancer 117, 1027-1037. doi: 10.1002/cncr.25531
52. Dawlaty, M. M., Breiling, A., Le, T., Raddatz, G., Inmaculada, M., Cheng, A. W., et al. (2014). Combined deficiency of Tet1 and Tet2 causes epigenetic abnormalities but is compatible with postnatal development. Dev. Cell 24, 310-323. doi: 10.1016/j.devcel.2012.12.015.Combined
53. Dawlaty, M. M., Ganz, K., Powell, B. E., Hu, Y. C., Markoulaki, S., Cheng, A. W., et al. (2011). Tet1 is dispensable for maintaining pluripotency and its loss is compatible with embryonic and postnatal development. Cell Stem Cell 9, 166-175. doi: 10.1016/j.stem.2011.07.010
54. de Rojas-Walker, T., Tamir, S., Ji, H., Wishnok, J. S., and Tannenbaum, S. R. (1995). Nitric oxide induces oxidative damage in addition to deamination in macrophage DNA. Chem. Res. Toxicol. 8, 473-477. doi: 10.1021/tx00045a020
55. Deplus, R., Delatte, B., Schwinn, M. K., Defrance, M., Mendez, J., Murphy, N., et al. (2013). TET2 and TET3 regulate GlcNAcylation and H3K4 methylation through OGT and SET1/COMPASS. EMBO J. 32, 645-655. doi: 10.1038/emboj.2012.357
56. Doege, C. A., Inoue, K., Yamashita, T., Rhee, D. B., Travis, S., Fujita, R., et al. (2012). Early-stage epigenetic modification during somatic cell reprogramming by Parp1 and Tet2. Nature 488, 652-655. doi: 10.1038/nature11333
57. dos Santos, R. L., Tosti, L., Radzisheuskaya, A., Caballero, I. M., Kaji, K., Hendrich, B., et al. (2014). MBD3/NuRD facilitates induction of pluripotency in a context-dependent manner. Cell Stem Cell 15, 102-110. doi: 10.1016/j.stem.2014.04.019
58. Dragich, J. M., Kim, Y. H., Arnold, A. P., and Schanen, N. C. (2007). Differential distribution of the MeCP2 splice variants in the postnatal mouse brain. J. Comp. Neurol. 501, 526-542. doi: 10.1002/cne.21264
59. Easwaran, H. P., Schermelleh, L., Leonhardt, H., and Cardoso, M. C. (2004). Replication-independent chromatin loading of Dnmt1 during G2 and M phases. EMBO Rep. 5, 1181-1186. doi: 10.1038/sj.embor.7400295
60. Ebert, D. H., Gabel, H. W., Robinson, N. D., Kastan, N. R., Hu, L. S., Cohen, S., et al. (2013). Activity-dependent phosphorylation of MeCP2 threonine 308 regulates interaction with NCoR. Nature 499, 341-345. doi: 10.1038/nature12348
61. Filion, G. J., Zhenilo, S., Salozhin, S., Yamada, D., Prokhortchouk, E., and Defossez, P. A. (2006). A family of human zinc finger proteins that bind methylated DNA and repress transcription. Mol. Cell. Biol. 26, 169-181. doi: 10.1128/MCB.26.1.169-181.2006
62. Frauer, C., Hoffmann, T., Bultmann, S., Casa, V., Cardoso, M. C., Antes, I., et al. (2011a). Recognition of 5-hydroxymethylcytosine by the Uhrf1 SRA domain. PLoS ONE 6:e21306. doi: 10.1371/journal.pone.0021306
63. Frauer, C., Rottach, A., Meilinger, D., Bultmann, S., Fellinger, K., Hasenöder, S., et al. (2011b). Different binding properties and function of CXXC zinc finger domains in Dnmt1 and Tet1. PLoS ONE 6:e16627. doi: 10.1371/journal.pone.0016627
64. Fujimori, A., Matsuda, Y., Takemoto, Y., Hashimoto, Y., Kubo, E., Araki, R., et al. (1998). Cloning and mapping of Np95 gene which encodes a novel nuclear protein associated with cell proliferation. Mamm. Genome 9, 1032-1035. doi: 10.1007/s003359900920
65. Fujita, N., Takebayashi, S., Okumura, K., Kudo, S., Chiba, T., Saya, H., et al. (1999). Methylation-mediated transcriptional silencing in euchromatin by methyl-CpG binding protein MBD1 isoforms. Mol. Cell. Biol. 19, 6415-6426. doi: 10.1128/MCB.19.9.6415
66. Fujita, N., Watanabe, S., Ichimura, T., Tsuruzoe, S., Shinkai, Y., Tachibana, M., et al. (2003). Methyl-CpG binding domain 1 (MBD1) interacts with the Suv39h1-HP1 heterochromatic complex for DNA methylation-based transcriptional repression. J. Biol. Chem. 278, 24132-24138. doi: 10.1074/jbc. M302283200
67. Fuks, F., Hurd, P. J., Wolf, D., Nan, X., Bird, A. P., and Kouzarides, T. (2003). The methyl-CpG-binding protein MeCP2 links DNA methylation to histone methylation. J. Biol. Chem. 278, 4035-4040. doi: 10.1074/jbc. M210256200
68. Gao, Y., Chen, J., Li, K., Wu, T., Huang, B., Liu, W., et al. (2013). 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. doi: 10.1016/j.stem.2013.02.005
69. Georgel, P. T., Horowitz-Scherer, R. A., Adkins, N., Woodcock, C. L., Wade, P. A., and Hansen, J. C. (2003). Chromatin compaction by human MeCP2. Assembly of novel secondary chromatin structures in the absence of DNA methylation. J. Biol. Chem. 278, 32181-32188. doi: 10.1074/jbc. M305308200
70. Ghosh, R. P., Nikitina, T., Horowitz-Scherer, R. A., Gierasch, L. M., Uversky, V. N., Hite, K., et al. (2010). Unique physical properties and interactions of the domains of methylated DNA binding protein 2. Biochemistry 49, 4395-4410. doi: 10.1021/bi9019753
71. Gnanapragasam, M. N., Scarsdale, J. N., Amaya, M. L., Webb, H. D., Desai, M. A., Walavalkar, N. M., et al. (2011). p66Alpha-MBD2 coiled-coil interaction and recruitment of Mi-2 are critical for globin gene silencing by the MBD2-NuRD complex. Proc. Natl. Acad. Sci. U.S.A. 108, 7487-7492. doi: 10.1073/pnas.1015341108
72. Goll, M. G., Kirpekar, F., Maggert, K. A., Yoder, J. A., Hsieh, C.-L., Zhang, X., et al. (2006). Methylation of tRNAAsp by the DNA methyltransferase homolog Dnmt2. Science 311, 395-398. doi: 10.1126/science.1120976
73. Gonzales, M. L., Adams, S., Dunaway, K. W., and LaSalle, J. M. (2012). Phosphorylation of distinct sites in MeCP2 modifies cofactor associations and the dynamics of transcriptional regulation. Mol. Cell. Biol. 32, 2894-2903. doi: 10.1128/MCB.06728-11
74. Grohmann, M., Spada, F., Schermelleh, L., Alenina, N., Bader, M., Cardoso, M. C., et al. (2005). Restricted mobility of Dnmt1 in preimplantation embryos: implications for epigenetic reprogramming. BMC Dev. Biol. 5:18. doi: 10.1186/1471-213X-5-18
75. Gu, T. P., Guo, F., Yang, H., Wu, H. P., Xu, G. F., Liu, W., et al. (2011). The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes. Nature 477, 606-610. doi: 10.1038/nature10443
76. Gunther, K., Rust, M., Leers, J., Boettger, T., Scharfe, M., Jarek, M., et al. (2013). Differential roles for MBD2 and MBD3 at methylated CpG islands, active promoters and binding to exon sequences. Nucleic Acids Res. 41, 3010-3021. doi: 10.1093/nar/gkt035
77. Guo, J. U., Su, Y., Shin, J. H., Shin, J., Li, H., Xie, B., et al. (2014). Distribution, recognition and regulation of non-CpG methylation in the adult mammalian brain. Nat. Neurosci. 17, 215-222. doi: 10.1038/nn.3607
78. Guo, J. U., Su, Y., Zhong, C., Ming, G. L., and Song, H. (2011). Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell 145, 423-434. doi: 10.1016/j.cell.2011.03.022
79. Guy, J., Gan, J., Selfridge, J., Cobb, S., and Bird, A. (2007). Reversal of neurological defects in a mouse model of Rett syndrome. Science 315, 1143-1147. doi: 10.1126/science.1138389
80. Guy, J., Hendrich, B., Holmes, M., Martin, J. E., and Bird, A. (2001). A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat. Genet. 27, 322-326. doi: 10.1038/85899
81. Hackett, J. A., Sengupta, R., Zylicz, J. J., Murakami, K., Lee, C., Down, T. A., et al. (2013). Germline DNA demethylation dynamics and imprint erasure through 5-hydroxymethylcytosine. Science 339, 448-452. doi: 10.1126/science.1229277
82. Haffner, M. C., Chaux, A., Meeker, A. K., Esopi, D. M., Gerber, J., Pellakuru, L. G., et al. (2011). Global 5-hydroxymethylcytosine content is significantly reduced in tissue stem/progenitor cell compartments and in human cancers. Oncotarget 2, 627-637. doi: 10.18632/oncotarget.316
83. Hagberg, B., Aicardi, J., Dias, K., and Ramos, O. (1983). A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: rett's syndrome: report of 35 cases. Ann. Neurol. 14, 471-479. doi: 10.1002/ana.410140412
84. Hajkova, P., Erhardt, S., Lane, N., Haaf, T., El-Maarri, O., Reik, W., et al. (2002). Epigenetic reprogramming in mouse primordial germ cells. Mech. Dev. 117, 15-23. doi: 10.1016/S0925-4773(02)00181-8
85. Hamiche, A., Schultz, P., Ramakrishnan, V., Oudet, P., and Prunell, A. (1996). Linker histone-dependent DNA structure in linear mononucleosomes. J. Mol. Biol. 257, 30-42. doi: 10.1006/jmbi.1996.0144
86. Hansen, R. S., Wijmenga, C., Luo, P., Stanek, A. M., Canfield, T. K., Weemaes, C. M., et al. (1999). The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. Proc. Natl. Acad. Sci. U.S.A. 96, 14412-14417. doi: 10.1073/pnas.96.25.14412
87. Hashimoto, H., Horton, J. R., Zhang, X., Bostick, M., Jacobsen, S. E., and Cheng, X. (2008). The SRA domain of UHRF1 flips 5-methylcytosine out of the DNA helix. Nature 455, 826-829. doi: 10.1038/nature07280
88. Hashimoto, H., Horton, J. R., Zhang, X., and Cheng, X. (2009). UHRF1, a modular multi-domain protein, regulates replication-coupled crosstalk between DNA methylation and histone modifications. Epigenetics 4, 8-14. doi: 10.4161/epi.4.1.7370
89. Hashimoto, H., Liu, Y., Upadhyay, A. K., Chang, Y., Howerton, S. B., Vertino, P. M., et al. (2012a). Recognition and potential mechanisms for replication and erasure of cytosine hydroxymethylation. Nucleic Acids Res. 40, 4841-4849. doi: 10.1093/nar/gks155
90. Hashimoto, H., Pais, J. E., Dai, N., Corrêa, I. R., Zhang, X., Zheng, Y., et al. (2015). Structure of Naegleria Tet-like dioxygenase (NgTet1) in complexes with a reaction intermediate 5-hydroxymethylcytosine DNA. Nucleic Acids Res. 43, 10713-10721. doi: 10.1093/nar/gkv870
91. Hashimoto, H., Pais, J. E., Zhang, X., Saleh, L., Fu, Z. Q., Dai, N., et al. (2014). Structure of a Naegleria Tet-like dioxygenase in complex with 5-methylcytosine DNA. Nature 506, 391-395. doi: 10.1038/nature12905
92. Hashimoto, H., Zhang, X., and Cheng, X. (2012b). Excision of thymine and 5-hydroxymethyluracil by the MBD4 DNA glycosylase domain: structural basis and implications for active DNA demethylation. Nucleic Acids Res. 40, 8276-8284. doi: 10.1093/nar/gks628
93. He, X., Duan, C., Chen, J., Ou-Yang, X., Zhang, Z., Li, C., et al. (2009). Let-7a elevates p21(WAF1) levels by targeting of NIRF and suppresses the growth of A549 lung cancer cells. FEBS Lett. 583, 3501-3507. doi: 10.1016/j.febslet.2009.10.007
94. He, Y. F., Li, B. Z., Li, Z., Liu, P., Wang, Y., Tang, Q., et al. (2011). Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 333, 1303-1307. doi: 10.1126/science.1210944
95. Hendrich, B., and Bird, A. (1998). Identification and characterization of a family of mammalian methyl-CpG binding proteins. Mol. Cell. Biol. 18, 6538-6547. doi: 10.1128/MCB.18.11.6538
96. Hendrich, B., Guy, J., Ramsahoye, B., Wilson, V. A., and Bird, A. (2001). Closely related proteins MBD2 and MBD3 play distinctive but interacting roles in mouse development. Genes Dev. 15, 710-723. doi: 10.1101/gad.194101
97. Hendrich, B., Hardeland, U., Ng, H. H., Jiricny, J., and Bird, A. (1999). The thymine glycosylase MBD4 can bind to the product of deamination at methylated CpG sites. Nature 401, 301-304. doi: 10.1038/45843
98. Hendrich, B., and Tweedie, S. (2003). The methyl-CpG binding domain and the evolving role of DNA methylation in animals. Trends Genet. 19, 269-277. doi: 10.1016/S0168-9525(03)00080-5
99. Hopfner, R., Mousli, M., Jeltsch, J. M., Voulgaris, A., Lutz, Y., Marin, C., et al. (2000). ICBP90, a novel human CCAAT binding protein, involved in the regulation of topoisomerase IIalpha expression. Cancer Res. 60, 121-128.
100. Hotchkiss, D. (1948). THE QUANTITATIVE SEPARATION OF PURINES, and NUCLEOSIDES BY paper chromatography. J. Biol. Chem. 175, 315-332.
101. Hu, L., Li, Z., Cheng, J., Rao, Q., Gong, W., Liu, M., et al. (2013). Crystal structure of TET2-DNA complex: insight into TET-mediated 5mC oxidation. Cell 155, 1545-1555. doi: 10.1016/j.cell.2013.11.020
102. Hu, L., Li, Z., Wang, P., Lin, Y., and Xu, Y. (2011). Crystal structure of PHD domain of UHRF1 and insights into recognition of unmodified histone H3 arginine residue 2. Cell Res. 21, 1374-1378. doi: 10.1038/cr.2011.124
103. Hu, L., Lu, J., Cheng, J., Rao, Q., Li, Z., Hou, H., et al. (2015). Structural insight into substrate preference for TET-mediated oxidation. Nature 527, 118-122. doi: 10.1038/nature15713
104. Hu, Y. G., Hirasawa, R., Hu, J. L., Hata, K., Li, C. L., Jin, Y., et al. (2008). Regulation of DNA methylation activity through Dnmt3L promoter methylation by Dnmt3 enzymes in embryonic development. Hum. Mol. Genet. 17, 2654-2664. doi: 10.1093/hmg/ddn165
105. Huang, H., Jiang, X., Li, Z., Li, Y., Song, C.-X., He, C., et al. (2013). TET1 plays an essential oncogenic role in MLL-rearranged leukemia. Proc. Natl. Acad. Sci. U.S.A. 110, 11994-11999. doi: 10.1073/pnas.1310656110
106. Huang, Y., Chavez, L., Chang, X., Wang, X., Pastor, W. A., Kang, J., et al. (2014). Distinct roles of the methylcytosine oxidases Tet1 and Tet2 in mouse embryonic stem cells. Proc. Natl. Acad. Sci. U.S.A. 111, 1361-1366. doi: 10.1073/pnas.1322921111
107. Inano, K., Suetake, I., Ueda, T., Miyake, Y., Nakamura, M., Okada, M., et al. (2000). Maintenance-type DNA methyltransferase is highly expressed in post-mitotic neurons and localized in the cytoplasmic compartment. J. Biochem. 128, 315-321. doi: 10.1093/oxfordjournals.jbchem.a022755
108. Iqbal, K., Jin, S. G., Pfeifer, G. P., and Szabo, P. E. (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. doi: 10.1073/pnas.1014033108
109. Ito, R., Katsura, S., Shimada, H., Tsuchiya, H., Hada, M., Okumura, T., et al. (2014). TET3-OGT interaction increases the stability and the presence of OGT in chromatin. Genes Cells 19, 52-65. doi: 10.1111/gtc.12107
110. Ito, S., D'Alessio, A. C., Taranova, O. V., Hong, K., Sowers, L. C., and 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. doi: 10.1038/nature09303
111. Ito, S., Shen, L., Dai, Q., Wu, S. C., Collins, L. B., Swenberg, J. A., et al. (2011). Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333, 1300-1303. doi: 10.1126/science.1210597
112. Jin, C., Lu, Y., Jelinek, J., Liang, S., Estecio, M. R. H., Barton, M. C., et al. (2014). TET1 is a maintenance DNA demethylase that prevents methylation spreading in differentiated cells. Nucleic Acids Res. 42, 6956-6971. doi: 10.1093/nar/gku372
113. Jin, S. G., Wu, X., Li, A. X., and Pfeifer, G. P. (2011). Genomic mapping of 5-hydroxymethylcytosine in the human brain. Nucleic Acids Res. 39, 5015-5024. doi: 10.1093/nar/gkr120
114. Johnson, L. M., Bostick, M., Zhang, X., Kraft, E., Henderson, I., Callis, J., et al. (2007). The SRA methyl-cytosine-binding domain links DNA and histone methylation. Curr. Biol. 17, 379-384. doi: 10.1016/j.cub.2007.01.009
115. Jones, P. L., Veenstra, G. J., Wade, P. A., Vermaak, D., Kass, S. U., Landsberger, N., et al. (1998). Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat. Genet. 19, 187-191. doi: 10.1038/561
116. Jorgensen, H. F., Ben-Porath, I., and Bird, A. P. (2004). Mbd1 is recruited to both methylated and nonmethylated CpGs via distinct DNA binding domains. Mol. Cell. Biol. 24, 3387-3395. doi: 10.1128/MCB.24.8.3387-3395.2004
117. Jung, B. P., Jugloff, D. G., Zhang, G., Logan, R., Brown, S., and Eubanks, J. H. (2003). The expression of methyl CpG binding factor MeCP2 correlates with cellular differentiation in the developing rat brain and in cultured cells. J. Neurobiol. 55, 86-96. doi: 10.1002/neu.10201
118. Jung, S. Y., Li, Y., Wang, Y., Chen, Y., Zhao, Y., and Qin, J. (2008). Complications in the assignment of 14 and 28 Da mass shift detected by mass spectrometry as in vivo methylation from endogenous proteins. Anal. Chem. 80, 1721-1729. doi: 10.1021/ac7021025
119. Kaji, K., Caballero, I. M., MacLeod, R., Nichols, J., Wilson, V. A., and Hendrich, B. (2006). The NuRD component Mbd3 is required for pluripotency of embryonic stem cells. Nat. Cell Biol. 8, 285-292. doi: 10.1038/ncb1372
120. Kaludov, N. K., and Wolffe, A. P. (2000). MeCP2 driven transcriptional repression in vitro: selectivity for methylated DNA, action at a distance and contacts with the basal transcription machinery. Nucleic Acids Res. 28, 1921-1928. doi: 10.1093/nar/28.9.1921
121. Karagianni, P., Amazit, L., Qin, J., and Wong, J. (2008). ICBP90, a novel methyl K9 H3 binding protein linking protein ubiquitination with heterochromatin formation. Mol. Cell. Biol. 28, 705-717. doi: 10.1128/MCB.01598-07
122. Kemmerich, K., Dingler, F. A., Rada, C., and Neuberger, M. S. (2012). Germline ablation of SMUG1 DNA glycosylase causes loss of 5-hydroxymethyluracil-and UNG-backup uracil-excision activities and increases cancer predisposition of Ung-/-Msh2-/-mice. Nucleic Acids Res. 40, 6016-6025. doi: 10.1093/nar/gks259
123. Kiefer, H., Chatail-Hermitte, F., Ravassard, P., Bayard, E., Brunet, I., and Mallet, J. (2005). ZENON, a novel POZ Kruppel-like DNA binding protein associated with differentiation and/or survival of late postmitotic neurons. Mol. Cell. Biol. 25, 1713-1729. doi: 10.1128/MCB.25.5.1713-1729.2005
124. Kienhöfer, S., Musheev, M. U., Stapf, U., Helm, M., Schomacher, L., Niehrs, C., et al. (2015). GADD45a physically and functionally interacts with TET1. Differentiation 90, 59-68. doi: 10.1016/j.diff.2015.10.003
125. Kim, J. K., Esteve, P. O., Jacobsen, S. E., and Pradhan, S. (2009). UHRF1 binds G9a and participates in p21 transcriptional regulation in mammalian cells. Nucleic Acids Res. 37, 493-505. doi: 10.1093/nar/gkn961
126. Kim, S. W., Park, J. I., Spring, C. M., Sater, A. K., Ji, H., Otchere, A. A., et al. (2004). Non-canonical Wnt signals are modulated by the Kaiso transcriptional repressor and p120-catenin. Nat. Cell Biol. 6, 1212-1220. doi: 10.1038/ncb1191
127. Kimura, H., and Shiota, K. (2003). Methyl-CpG-binding protein, MeCP2, is a target molecule for maintenance DNA methyltransferase, Dnmt1. J. Biol. Chem. 278, 4806-4812. doi: 10.1074/jbc. M209923200
128. Klein, C. J., Bird, T., Ertekin-Taner, N., Lincoln, S., Hjorth, R., Wu, Y., et al. (2013). DNMT1 mutation hot spot causes varied phenotypes of HSAN1 with dementia and hearing loss. Neurology 80, 824-828. doi: 10.1212/WNL.0b013e31828
129. Klein, C. J., Botuyan, M. V., Wu, Y., Ward, C. J., Nicholson, G. A., Hammans, S., et al. (2011). Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss. Nat. Genet. 43, 595-600. doi: 10.1038/ng.830
130. Ko, M., An, J., Bandukwala, H. S., Chavez, L., Aijö, T., Pastor, W. A., et al. (2013). Modulation of TET2 expression and 5-methylcytosine oxidation by the CXXC domain protein IDAX. Nature 497, 122-126. doi: 10.1038/nature12052
131. Ko, M., Huang, Y., Jankowska, A. M., Pape, U. J., Tahiliani, M., Bandukwala, H. S., et al. (2010). Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature 468, 839-843. doi: 10.1038/nature09586
132. Kokura, K., Kaul, S. C., Wadhwa, R., Nomura, T., Khan, M. M., Shinagawa, T., et al. (2001). The Ski protein family is required for MeCP2-mediated transcriptional repression. J. Biol. Chem. 276, 34115-34121. doi: 10.1074/jbc. M105747200
133. Konstandin, N., Bultmann, S., Szwagierczak, A., Dufour, A., Ksienzyk, B., Schneider, F., et al. (2011). Genomic 5-hydroxymethylcytosine levels correlate with TET2 mutations and a distinct global gene expression pattern in secondary acute myeloid leukemia. Leukemia 25, 1649-1652. doi: 10.1038/leu.2011.134leu2011134
134. Koziol, M. J., Bradshaw, C. R., Allen, G. E., Costa, A. S., Frezza, C., and Gurdon, J. B. (2016). Identification of methylated deoxyadenosines in vertebrates reveals diversity in DNA modifications. Nat. Struct. Mol. Biol. 23, 24-30. doi: 10.1038/nsmb.3145
135. Kraus, T. F. J., Globisch, D., Wagner, M., Eigenbrod, S., Widmann, D., Münzel, M., et al. (2012). Low values of 5-hydroxymethylcytosine (5hmC), the "sixth base, "are associated with anaplasia in human brain tumors. Int. J. Cancer 131, 1577-1590. doi: 10.1002/ijc.27429
136. Kriaucionis, S., and Bird, A. (2004). The major form of MeCP2 has a novel N-terminus generated by alternative splicing. Nucleic Acids Res. 32, 1818-1823. doi: 10.1093/nar/gkh349
137. Kriaucionis, S., and Heintz, N. (2009). The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science 324, 929-930. doi: 10.1126/science.1169786
138. Kumar, S., Cheng, X., Klimasauskas, S., Mi, S., Posfai, J., Roberts, R. J., et al. (1994). The DNA (cytosine-5) methyltransferases. Nucleic Acids Res. 22, 1-10. doi: 10.1093/nar/22.1.1
139. Laget, S., Joulie, M., Le Masson, F., Sasai, N., Christians, E., Pradhan, S., et al. (2010). The human proteins MBD5 and MBD6 associate with heterochromatin but they do not bind methylated DNA. PLoS ONE 5:e11982. doi: 10.1371/journal.pone.0011982
140. Ley, T. J., Ding, L., Walter, M. J., McLellan, M. D., Lamprecht, T., Larson, D. E., et al. (2011). DNMT3A Mutations in Acute Myeloid Leukemia. N. Engl. J. Med. 363, 2424-2433. doi: 10.1056/NEJMoa1005143
141. Langemeijer, S., Kuiper, R., Berends, M., Knops, R., Aslanyan, M., Massop, M., et al. (2009). Acquired mutations in TET2 are common in myelodysplastic syndromes. Leuk. Res. 33, 838-842. doi: 10.1016/S0145-2126(09)70132-8
142. Le Guezennec, X., Vermeulen, M., Brinkman, A. B., Hoeijmakers, W. A., Cohen, A., Lasonder, E., et al. (2006). MBD2/NuRD and MBD3/NuRD, two distinct complexes with different biochemical and functional properties. Mol. Cell. Biol. 26, 843-851. doi: 10.1128/MCB.26.3.843-851.2006
143. Lee, J. H., and Skalnik, D. G. (2002). CpG-binding protein is a nuclear matrix-and euchromatin-associated protein localized to nuclear speckles containing human trithorax. Identification of nuclear matrix targeting signals. J. Biol. Chem. 277, 42259-42267. doi: 10.1074/jbc. M205054200
144. Lee, J. H., and Skalnik, D. G. (2005). 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. doi: 10.1074/jbc. M508312200
145. Leonhardt, H., Page, A. W., Weier, H. U., and Bestor, T. H. (1992). A targeting sequence directs DNA methyltransferase to sites of DNA replication in mammalian nuclei. Cell 71, 865-873. doi: 10.1016/0092-8674(92)90561-P
146. Lewis, J. D., Meehan, R. R., Henzel, W. J., Maurer-Fogy, I., Jeppesen, P., Klein, F., et al. (1992). Purification, sequence, and cellular localization of a novel chromosomal protein that binds to methylated DNA. Cell 69, 905-914. doi: 10.1016/0092-8674(92)90610-O
147. Li, D., Qiu, Z., Shao, Y., Chen, Y., Guan, Y., Liu, M., et al. (2013). Heritable gene targeting in the mouse and rat using a CRISPR-Cas system. Nat. Biotechnol. 31, 681-683. doi: 10.1038/nbt.2661
148. Li, E., Bestor, T. H., and Jaenisch, R. (1992). Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69, 915-926. doi: 10.1016/0092-8674(92)90611-F
149. Li, H., and Chang, Q. (2014). Regulation and function of stimulus-induced phosphorylation of MeCP2. Front. Biol. (Beijing) 9:367-375. doi: 10.1007/s11515-014-1330-2
150. Li, W., and Liu, M. (2011). Distribution of 5-hydroxymethylcytosine in different human tissues. J. Nucleic Acids 2011, 870726. doi: 10.4061/2011/870726
151. Li, Z., Cai, X., Cai, C. L., Wang, J., Zhang, W., Petersen, B. E., et al. (2011). Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies. Blood 118, 4509-4518. doi: 10.1182/blood-2010-12-325241
152. Li, Z., Gu, T. P., Weber, A. R., Shen, J. Z., Li, B. Z., Xie, Z. G., et al. (2015). Gadd45a promotes DNA demethylation through TDG. Nucleic Acids Res. 43, 3986-3997. doi: 10.1093/nar/gkv283
153. Lin, R. K., Hsu, H. S., Chang, J. W., Chen, C. Y., Chen, J. T., and Wang, Y. C. (2007). Alteration of DNA methyltransferases contributes to 5'CpG methylation and poor prognosis in lung cancer. Lung Cancer 55, 205-213. doi: 10.1016/j.lungcan.2006.10.022
154. Liu, N., Wang, M., Deng, W., Schmidt, C. S., Qin, W., Leonhardt, H., et al. (2013). Intrinsic and extrinsic connections of Tet3 dioxygenase with CXXC zinc finger modules. PLoS ONE 8:e62755. doi: 10.1371/journal.pone.0062755
155. Liu, Y., Oakeley, E. J., Sun, L., and Jost, J. P. (1998). Multiple domains are involved in the targeting of the mouse DNA methyltransferase to the DNA replication foci. Nucleic Acids Res. 26, 1038-1045. doi: 10.1093/nar/26.4.1038
156. Loat, C. S., Curran, S., Lewis, C. M., Duvall, J., Geschwind, D., Bolton, P., et al. (2008). Methyl-CpG-binding protein 2 polymorphisms and vulnerability to autism. Genes Brain Behav. 7, 754-760. doi: 10.1111/j.1601-183X.2008.00414.x
157. Lopes, E. C., Valls, E., Figueroa, M. E., Mazur, A., Meng, F. G., Chiosis, G., et al. (2008). Kaiso contributes to DNA methylation-dependent silencing of tumor suppressor genes in colon cancer cell lines. Cancer Res. 68, 7258-7263. doi: 10.1158/0008-5472.CAN-08-0344
158. Lorsbach, R. B., Moore, J., Mathew, S., Raimondi, S. C., Mukatira, S. T., and Downing, J. R. (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. doi: 10.1038/sj.leu.2402834
159. Lu, J., Hu, L., Cheng, J., Dong, F., Wang, C., Yu, K., et al. (2016). A computational investigation on the substrate preference of TET2. Phys. Chem. Chem. Phys 18, 4728-4738. doi: 10.1039/C5CP07266B
160. Lunyak, V. V., Burgess, R., Prefontaine, G. G., Nelson, C., Sze, S. H., Chenoweth, J., et al. (2002). Corepressor-dependent silencing of chromosomal regions encoding neuronal genes. Science 298, 1747-1752. doi: 10.1126/science.1076469
161. Luo, M., Ling, T., Xie, W., Sun, H., Zhou, Y., Zhu, Q., et al. (2013). NuRD blocks reprogramming of mouse somatic cells into pluripotent stem cells. Stem Cells 31, 1278-1286. doi: 10.1002/stem.1374
162. Lyko, F., Ramsahoye, B. H., and Jaenisch, R. (2000). DNA methylation in Drosophila melanogaster. Nature 408, 538-540. doi: 10.1038/35046205
163. Lyst, M. J., Ekiert, R., Ebert, D. H., Merusi, C., Nowak, J., Selfridge, J., et al. (2013). Rett syndrome mutations abolish the interaction of MeCP2 with the NCoR/SMRT co-repressor. Nat. Neurosci. 16, 898-902. doi: 10.1038/nn.3434
164. Lyst, M. J., Nan, X., and Stancheva, I. (2006). Regulation of MBD1-mediated transcriptional 1478 repression by SUMO and PIAS proteins. EMBO J. 25, 5317-5328. doi: 10.1038/sj.emboj.7601404
165. Mahajan, M. C., Narlikar, G. J., Boyapaty, G., Kingston, R. E., and Weissman, S. M. (2005). Heterogeneous nuclear ribonucleoprotein C1/C2, MeCP1, and SWI/SNF form a chromatin remodeling complex at the beta-globin locus control region. Proc. Natl. Acad. Sci. U.S.A. 102, 15012-15017. doi: 10.1073/pnas.0507596102
166. Maiti, A., and Drohat, A. C. (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. doi: 10.1074/jbc. C111.284620
167. Marhold, J., Kramer, K., Kremmer, E., and Lyko, F. (2004). The Drosophila MBD2/3 protein mediates interactions between the MI-2 chromatin complex and CpT/A-methylated DNA. Development 131, 6033-6039. doi: 10.1242/dev.01531
168. Martinowich, K., Hattori, D., Wu, H., Fouse, S., He, F., Hu, Y., et al. (2003). DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science 302, 890-893. doi: 10.1126/science.1090842
169. Mayer, W., Niveleau, A., Walter, J., Fundele, R., and Haaf, T. (2000). Demethylation of the zygotic paternal genome. Nature 403, 501-502. doi: 10.1038/35000654
170. Meehan, R. R., Lewis, J. D., and Bird, A. P. (1992). Characterization of MeCP2, a vertebrate DNA binding protein with affinity for methylated DNA. Nucleic Acids Res. 20, 5085-5092. doi: 10.1093/nar/20.19.5085
171. Meehan, R. R., Lewis, J. D., McKay, S., Kleiner, E. L., and Bird, A. P. (1989). Identification of a mammalian protein that binds specifically to DNA containing methylated CpGs. Cell 58, 499-507. doi: 10.1016/0092-8674(89)90430-3
172. Meilinger, D., Fellinger, K., Bultmann, S., Rothbauer, U., Bonapace, I. M., Klinkert, W. E., et al. (2009). Np95 interacts with de novo DNA methyltransferases, Dnmt3a and Dnmt3b, and mediates epigenetic silencing of the viral CMV promoter in embryonic stem cells. EMBO Rep. 10, 1259-1264. doi: 10.1038/embor.2009.201
173. Mellen, M., Ayata, P., Dewell, S., Kriaucionis, S., and Heintz, N. (2012). MeCP2 binds to 5hmC enriched within active genes and accessible chromatin in the nervous system. Cell 151, 1417-1430. doi: 10.1016/j.cell.2012.11.022
174. Mertineit, C., Yoder, J. A., Taketo, T., Laird, D. W., Trasler, J. M., and Bestor, T. H. (1998). Sex-specific exons control DNA methyltransferase in mammalian germ cells. Development 125, 889-897.
175. Michaels, M. L., Pham, L., Nghiem, Y., Cruz, C., and Miller, J. H. (1990). MutY, an adenine glycosylase active on G-A mispairs, has homology to endonuclease III. Nucleic Acids Res. 18, 3841-3845. doi: 10.1093/nar/18.13.3841
176. Millar, C. B., Guy, J., Sansom, O. J., Selfridge, J., MacDougall, E., Hendrich, B., et al. (2002). Enhanced CpG mutability and tumorigenesis in MBD4-deficient mice. Science 297, 403-405. doi: 10.1126/science.1073354
177. Mnatzakanian, G. N., Lohi, H., Munteanu, I., Alfred, S. E., Yamada, T., MacLeod, P. J., et al. (2004). A previously unidentified MECP2 open reading frame defines a new protein isoform relevant to Rett syndrome. Nat. Genet. 36, 339-341. doi: 10.1038/ng1327
178. Mori, T., Ikeda, D. D., Yamaguchi, Y., Unoki, M., and Project, N. (2012). NIRF/UHRF2 occupies a central position in the cell cycle network and allows coupling with the epigenetic landscape. FEBS Lett. 586, 1570-1583. doi: 10.1016/j.febslet.2012.04.038
179. Mori, T., Li, Y., Hata, H., Ono, K., and Kochi, H. (2002). NIRF, a novel RING finger protein, is involved in cell-cycle regulation. Biochem. Biophys. Res. Commun. 296, 530-536. doi: 10.1016/S0006-291X(02)00890-2
180. Muller, H. M., Fiegl, H., Goebel, G., Hubalek, M. M., Widschwendter, A., Muller-Holzner, E., et al. (2003). MeCP2 and MBD2 expression in human neoplastic and non-neoplastic breast tissue and its association with oestrogen receptor status. Br. J. Cancer 89, 1934-1939. doi: 10.1038/sj.bjc.6601392
181. Muller, U., Bauer, C., Siegl, M., Rottach, A., and Leonhardt, H. (2014). TET-mediated oxidation of methylcytosine causes TDG or NEIL glycosylase dependent gene reactivation. Nucleic Acids Res. 42, 8592-8604. doi: 10.1093/nar/gku552
182. Muotri, A. R., Marchetto, M. C., Coufal, N. G., Oefner, R., Yeo, G., Nakashima, K., et al. (2010). L1 retrotransposition in neurons is modulated by MeCP2. Nature 468, 443-446. doi: 10.1038/nature09544
183. Nady, N., Lemak, A., Walker, J. R., Avvakumov, G. V., Kareta, M. S., Achour, M., et al. (2011). Recognition of multivalent histone states associated with heterochromatin by UHRF1 protein. J. Biol. Chem. 286, 24300-24311. doi: 10.1074/jbc. M111.234104
184. Nagarajan, R. P., Hogart, A. R., Gwye, Y., Martin, M. R., and LaSalle, J. M. (2006). Reduced MeCP2 expression is frequent in autism frontal cortex and correlates with aberrant MECP2 promoter methylation. Epigenetics 1, e1-e11. doi: 10.4161/epi.1.4.3514
185. Nakagawa, T., Lv, L., Nakagawa, M., Yu, Y., Yu, C., D'Alessio, A. C., et al. (2015). CRL4VprBP E3 ligase promotes monoubiquitylation and chromatin binding of TET dioxygenases. Mol. Cell. 57, 247-260. doi: 10.1016/j.molcel.2014.12.002
186. Nakamura, T., Liu, Y. J., Nakashima, H., Umehara, H., Inoue, K., Matoba, S., et al. (2012). PGC7 binds histone H3K9me2 to protect against conversion of 5mC to 5hmC in early embryos. Nature 486, 415-419. doi: 10.1038/nature11093
187. Nan, X., Campoy, F. J., and Bird, A. (1997). MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin. Cell 88, 471-481. doi: 10.1016/S0092-8674(00)81887-5
188. Nan, X., Meehan, R. R., and Bird, A. (1993). Dissection of the methyl-CpG binding domain from the chromosomal protein MeCP2. Nucleic Acids Res. 21, 4886-4892. doi: 10.1093/nar/21.21.4886
189. Nan, X., Ng, H. H., Johnson, C. A., Laherty, C. D., Turner, B. M., Eisenman, R. N., et al. (1998). Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393, 386-389. doi: 10.1038/30764
190. Nestor, C. E., Ottaviano, R., Reddington, J., Sproul, D., Reinhardt, D., Dunican, D., et al. (2012). Tissue type is a major modifier of the 5-hydroxymethylcytosine content of human genes. Genome Res. 22, 467-477. doi: 10.1101/gr.126417.111
191. Ng, H. H., Jeppesen, P., and Bird, A. (2000). Active repression of methylated genes by the chromosomal protein MBD1. Mol. Cell. Biol. 20, 1394-1406. doi: 10.1128/MCB.20.4.1394-1406.2000
192. Ng, H. H., Zhang, Y., Hendrich, B., Johnson, C. A., Turner, B. M., Erdjument-Bromage, H., et al. (1999). MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex. Nat. Genet. 23, 58-61. doi: 10.1038/12659
193. Nikitina, T., Ghosh, R. P., Horowitz-Scherer, R. A., Hansen, J. C., Grigoryev, S. A., and Woodcock, C. L. (2007a). MeCP2-chromatin interactions include the formation of chromatosome-like structures and are altered in mutations causing Rett syndrome. J. Biol. Chem. 282, 28237-28245. doi: 10.1074/jbc. M704304200
194. Nikitina, T., Shi, X., Ghosh, R. P., Horowitz-Scherer, R. A., Hansen, J. C., and Woodcock, C. L. (2007b). Multiple modes of interaction between the methylated DNA binding protein MeCP2 and chromatin. Mol. Cell. Biol. 27, 864-877. doi: 10.1128/MCB.01593-06
195. Ohki, I., Shimotake, N., Fujita, N., Nakao, M., and Shirakawa, M. (1999). Solution structure of the methyl-CpG-binding domain of the methylation-dependent transcriptional repressor MBD1. EMBO J. 18, 6653-6661. doi: 10.1093/emboj/18.23.6653
196. Okano, M., Bell, D. W., Haber, D. A., and Li, E. (1999). DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99, 247-257. doi: 10.1016/S0092-8674(00)81656-6
197. Okano, M., Xie, S., and Li, E. (1998). Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nature Am. Inc. 19, 219-220. doi: 10.1038/890
198. Papait, R., Pistore, C., Grazini, U., Babbio, F., Cogliati, S., Pecoraro, D., et al. (2008). The PHD domain of Np95 (mUHRF1) is involved in large-scale reorganization of pericentromeric heterochromatin. Mol. Biol. Cell 19, 3554-3563. doi: 10.1091/mbc. E07-10-1059
199. Papait, R., Pistore, C., Negri, D., Pecoraro, D., Cantarini, L., and Bonapace, I. M. (2007). Np95 is implicated in pericentromeric heterochromatin replication and in major satellite silencing. Mol. Biol. Cell 18, 1098-1106. doi: 10.1091/mbc. E06-09-0874
200. Park, J. I., Kim, S. W., Lyons, J. P., Ji, H., Nguyen, T. T., Cho, K., et al. (2005). Kaiso/p120-catenin and TCF/beta-catenin complexes coordinately regulate canonical Wnt gene targets. Dev. Cell 8, 843-854. doi: 10.1016/j.devcel.2005.04.010
201. Pastor, W. A., Pape, U. J., Huang, Y., Henderson, H. R., Lister, R., Ko, M., et al. (2011). Genome-wide mapping of 5-hydroxymethylcytosine in embryonic stem cells. Nature 473, 394-397. doi: 10.1038/nature10102
202. Patra, S. K., Patra, A., Zhao, H., Carroll, P., and Dahiya, R. (2003). Methyl-CpG-DNA binding proteins in human prostate cancer: expression of CXXC sequence containing MBD1 and repression of MBD2 and MeCP2. Biochem. Biophys. Res. Commun. 302, 759-766. doi: 10.1016/S0006-291X(03)00253-5
203. Penn, N. W., Suwalski, R., O'Riley, C., Bojanowski, K., and Yura, R. (1972). The presence of 5-hydroxymethylcytosine in animal deoxyribonucleic acid. Biochem. J. 126, 781-790. doi: 10.1042/bj1260781
204. Petronzelli, F., Riccio, A., Markham, G. D., Seeholzer, S. H., Stoerker, J., Genuardi, M., et al. (2000). Biphasic kinetics of the human DNA repair protein MED1 (MBD4), a mismatch-specific DNA N-glycosylase. J. Biol. Chem. 275, 32422-32429. doi: 10.1074/jbc. M004535200
205. Pfaffeneder, T., Hackner, B., Truss, M., Münzel, M., Müller, M., Deiml, C. A., et al. (2011). The discovery of 5-formylcytosine in embryonic stem cell DNA. Angew. Chem. Int. Edn. 50, 7008-7012. doi: 10.1002/anie.201103899
206. Pfaffeneder, T., Spada, F., Wagner, M., Brandmayr, C., Laube, S. K., Eisen, D., et al. (2014). Tet oxidizes thymine to 5-hydroxymethyluracil in mouse embryonic stem cell DNA. Nat. Chem. Biol. 10, 574-581. doi: 10.1038/nchembio.1532
207. Pichler, G., Wolf, P., Schmidt, C. S., Meilinger, D., Schneider, K., Frauer, C., et al. (2011). Cooperative DNA and histone binding by Uhrf2 links the two major repressive epigenetic pathways. J. Cell. Biochem. 112, 2585-2593. doi: 10.1002/jcb.23185
208. Prokhortchouk, A., Hendrich, B., Jorgensen, H., Ruzov, A., Wilm, M., Georgiev, G., et al. (2001). The p120 catenin partner Kaiso is a DNA methylation-dependent transcriptional repressor. Genes Dev. 15, 1613-1618. doi: 10.1101/gad.198501
209. Prokhortchouk, A., Sansom, O., Selfridge, J., Caballero, I. M., Salozhin, S., Aithozhina, D., et al. (2006). Kaiso-deficient mice show resistance to intestinal cancer. Mol. Cell. Biol. 26, 199-208. doi: 10.1128/MCB.26.1.199-208.2006
210. Qin, W., Leonhardt, H., and Pichler, G. (2011). Regulation of DNA methyltransferase 1 by interactions and modifications. Nucleus 2, 392-402. doi: 10.4161/nucl.2.5.17928
211. Qiu, C., Sawada, K., Zhang, X., and Cheng, X. (2002). The PWWP domain of mammalian DNA methyltransferase Dnmt3b defines a new family of DNA-binding folds. Nat. Struct. Biol. 9, 217-224. doi: 10.1038/nsb759
212. Rais, Y., Zviran, A., Geula, S., Gafni, O., Chomsky, E., Viukov, S., et al. (2013). Deterministic direct reprogramming of somatic cells to pluripotency. Nature 502, 65-70. doi: 10.1038/nature12587
213. Rajakumara, E., Wang, Z., Ma, H., Hu, L., Chen, H., Lin, Y., et al. (2011). PHD finger recognition of unmodified histone H3R2 links UHRF1 to regulation of euchromatic gene expression. Mol. Cell. 43, 275-284. doi: 10.1016/j.molcel.2011.07.006
214. Ramocki, M. B., Peters, S. U., Tavyev, Y. J., Zhang, F., Carvalho, C. M., Schaaf, C. P., et al. (2009). Autism and other neuropsychiatric symptoms are prevalent in individuals with MeCP2 duplication syndrome. Ann. Neurol. 66, 771-782. doi: 10.1002/ana.21715
215. Razin, A., and Cedar, H. (1977). Distribution of 5-methylcytosine in chromatin. Proc. Natl. Acad. Sci. U.S.A. 74, 2725-2728. doi: 10.1073/pnas.74.7.2725
216. Rett, A. (1966). [On an until now unknown disease of a congenital metabolic disorder]. Krankenschwester 19, 121-122.
217. Reynolds, N., Latos, P., Hynes-Allen, A., Loos, R., Leaford, D., O'Shaughnessy, A., et al. (2012). NuRD suppresses pluripotency gene expression to promote transcriptional heterogeneity and lineage commitment. Cell Stem Cell 10, 583-594. doi: 10.1016/j.stem.2012.02.020
218. Riccio, A., Aaltonen, L. A., Godwin, A. K., Loukola, A., Percesepe, A., Salovaara, R., et al. (1999). The DNA repair gene MBD4 (MED1) is mutated in human carcinomas with microsatellite instability. Nat. Genet. 23, 266-268. doi: 10.1038/15443
219. Roll, J. D., Rivenbark, A. G., Jones, W. D., and Coleman, W. B. (2008). DNMT3b overexpression contributes to a hypermethylator phenotype in human breast cancer cell lines. Mol. Cancer 7, 15. doi: 10.1186/1476-4598-7-15
220. Roloff, T. C., Ropers, H. H., and Nuber, U. A. (2003). Comparative study of methyl-CpG-binding domain proteins. BMC Genomics 4:1. doi: 10.1186/1471-2164-4-1
221. Rothbart, S. B., Krajewski, K., Nady, N., Tempel, W., Xue, S., Badeaux, A. I., et al. (2012). Association of UHRF1 with methylated H3K9 directs the maintenance of DNA methylation. Nat. Struct. Mol. Biol. 19, 1155-1160. doi: 10.1038/nsmb.2391
222. Rottach, A., Frauer, C., Pichler, G., Bonapace, I. M., Spada, F., and Leonhardt, H. (2010). The multi-domain protein Np95 connects DNA methylation and histone modification. Nucleic Acids Res. 38, 1796-1804. doi: 10.1093/nar/gkp1152
223. Rountree, M. R., Bachman, K. E., and Baylin, S. B. (2000). DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. Nat. Genet. 25, 269-277. doi: 10.1038/77023
224. Rudenko, A., Dawlaty, M. M., Seo, J., Cheng, A. W., Meng, J., Le, T., et al. (2013). Tet1 is critical for neuronal activity-regulated gene expression and memory extinction. Neuron 79, 1109-1122. doi: 10.1016/j.neuron.2013.08.003
225. Saito, M., and Ishikawa, F. (2002). The mCpG-binding domain of human MBD3 does not bind to mCpG but interacts with NuRD/Mi2 components HDAC1 and MTA2. J. Biol. Chem. 277, 35434-35439. doi: 10.1074/jbc. M203455200
226. Sarraf, S. A., and Stancheva, I. (2004). 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. doi: 10.1016/j.molcel.2004.06.043
227. Sasai, N., Matsuda, E., Sarashina, E., Ishida, Y., and Kawaichi, M. (2005). Identification of a novel BTB-zinc finger transcriptional repressor, CIBZ, that interacts with CtBP corepressor. Genes Cells 10, 871-885. doi: 10.1111/j.1365-2443.2005.00885.x
228. Schermelleh, L., Haemmer, A., Spada, F., Rosing, N., Meilinger, D., Rothbauer, U., et al. (2007). Dynamics of Dnmt1 interaction with the replication machinery and its role in postreplicative maintenance of DNA methylation. Nucleic Acids Res. 35, 4301-4312. doi: 10.1093/nar/gkm432
229. Schlegel, J., Guneysu, S., and Mennel, H. D. (2002). Expression of the genes of methyl-binding domain proteins in human gliomas. Oncol. Rep. 9, 393-395.
230. Schneider, K., Fuchs, C., Dobay, A., Rottach, A., Qin, W., Wolf, P., et al. (2013). Dissection of cell cycle-dependent dynamics of Dnmt1 by FRAP and diffusion-coupled modeling. Nucleic Acids Res. 41, 4860-4876. doi: 10.1093/nar/gkt191
231. Shahbazian, M., Young, J., Yuva-Paylor, L., Spencer, C., Antalffy, B., Noebels, J., et al. (2002). Mice with truncated MeCP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3. Neuron 35, 243-254. doi: 10.1016/S0896-6273(02)00768-7
232. Sharif, J., Muto, M., Takebayashi, S., Suetake, I., Iwamatsu, A., Endo, T. A., et al. (2007). The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA. Nature 450, 908-912. doi: 10.1038/nature06397
233. Shibayama, A., Cook, E. H. Jr., Feng, J., Glanzmann, C., Yan, J., Craddock, N., et al. (2004). MECP2 structural and 3'-UTR variants in schizophrenia, autism and other psychiatric diseases: a possible association with autism. Am. J. Med. Genet. B Neuropsychiatr. Genet. 128B, 50-53. doi: 10.1002/ajmg.b.30016
234. Shimbo, T., Du, Y., Grimm, S. A., Dhasarathy, A., Mav, D., Shah, R. R., et al. (2013). MBD3 localizes at promoters, gene bodies and enhancers of active genes. PLoS Genet. 9:e1004028. doi: 10.1371/journal.pgen.1004028
235. Skene, P. J., Illingworth, R. S., Webb, S., Kerr, A. R., James, K. D., Turner, D. J., et al. (2010). Neuronal MeCP2 is expressed at near histone-octamer levels and globally alters the chromatin state. Mol. Cell. 37, 457-468. doi: 10.1016/j.molcel.2010.01.030
236. Song, J., Rechkoblit, O., Bestor, T. H., and Patel, D. J. (2011). Structure of DNMT1-DNA complex reveals a role for autoinhibition in maintenance DNA methylation. Science 331, 1036-1040. doi: 10.1126/science.1195380
237. Song, J., Teplova, M., Ishibe-Murakami, S., and Patel, D. J. (2012). Structure-based mechanistic insights into DNMT1-mediated maintenance DNA methylation. Science 335, 709-712. doi: 10.1126/science.1214453
238. Spruijt, C. G., Gnerlich, F., Smits, A. H., Pfaffeneder, T., Jansen, P. W., Bauer, C., et al. (2013). Dynamic readers for 5-(hydroxy)methylcytosine and its oxidized derivatives. Cell 152, 1146-1159. doi: 10.1016/j.cell.2013.02.004
239. Stancheva, I., Collins, A. L., Van den Veyver, I. B., Zoghbi, H., and Meehan, R. R. (2003). A mutant form of MeCP2 protein associated with human Rett syndrome cannot be displaced from methylated DNA by notch in Xenopus embryos. Mol. Cell. 12, 425-435. doi: 10.1016/S1097-2765(03)00276-4
240. Strichman-Almashanu, L. Z., Lee, R. S., Onyango, P. O., Perlman, E., Flam, F., Frieman, M. B., et al. (2002). A genome-wide screen for normally methylated human cpg islands that can identify novel imprinted genes a genome-wide screen for normally methylated human cpg islands that can identify novel imprinted genes. Genome Res 12, 543-554. doi: 10.1101/gr.224102
241. Su, L. K., Kinzler, K. W., Vogelstein, B., Preisinger, A. C., Moser, A. R., Luongo, C., et al. (1992). Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science 256, 668-670. doi: 10.1126/science.256.5060.1114-c
242. Suetake, I., Shinozaki, F., Miyagawa, J., Takeshima, H., and Tajima, S. (2004). DNMT3L stimulates the DNA methylation activity of Dnmt3a and Dnmt3b through a direct interaction. J. Biol. Chem. 279, 27816-27823. doi: 10.1074/jbc. M400181200
243. Suter, C. M., Martin, D. I., and Ward, R. L. (2004). Hypomethylation of L1 retrotransposons in colorectal cancer and adjacent normal tissue. Int. J. Colorectal. Dis. 19, 95-101. doi: 10.1007/s00384-003-0539-3
244. Szulwach, K. E., Li, X., Li, Y., Song, C. X., Wu, H., Dai, Q., et al. (2011). 5-hmC-mediated epigenetic dynamics during postnatal neurodevelopment and aging. Nat. Neurosci. 14, 1607-1616. doi: 10.1038/nn.2959
245. Tahiliani, M., Koh, K. P., Shen, Y., Pastor, W. A., Bandukwala, H., Brudno, Y., et al. (2009). Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324, 930-935. doi: 10.1126/science.1170116
246. Tardy-Planechaud, S., Fujimoto, J., Lin, S. S., and Sowers, L. C. (1997). Solid phase synthesis and restriction endonuclease cleavage of oligodeoxynucleotides containing 5-(hydroxymethyl)-cytosine. Nucleic Acids Res. 25, 553-559. doi: 10.1093/nar/25.3.553
247. Tatton-Brown, K., Seal, S., Ruark, E., Harmer, J., Ramsay, E., Del Vecchio Duarte, S., et al. (2014). Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability. Nat. Genet. 46, 385-388. doi: 10.1038/ng.2917
248. Traynor, J., Agarwal, P., Lazzeroni, L., and Francke, U. (2002). Gene expression patterns vary in clonal cell cultures from Rett syndrome females with eight different MECP2 mutations. BMC Med. Genet. 3:12. doi: 10.1186/1471-2350-3-12
249. Tsukada, Y., Fang, J., Erdjument-Bromage, H., Warren, M. E., Borchers, C. H., Tempst, P., et al. (2006). Histone demethylation by a family of JmjC domain-containing proteins. Nature 439, 811-816. doi: 10.1038/nature04433
250. Tucker, K. L., Talbot, D., Lee, M. A., Leonhardt, H., and Jaenisch, R. (1996). Complementation of methylation deficiency in embryonic stem cells by a DNA methyltransferase minigene. Proc. Natl. Acad. Sci. U.S.A. 93, 12920-12925. doi: 10.1073/pnas.93.23.12920
251. Tudor, M., Akbarian, S., Chen, R. Z., and Jaenisch, R. (2002). Transcriptional profiling of a mouse model for Rett syndrome reveals subtle transcriptional changes in the brain. Proc. Natl. Acad. Sci. U.S.A. 99, 15536-15541. doi: 10.1073/pnas.242566899
252. Uchimura, Y., Ichimura, T., Uwada, J., Tachibana, T., Sugahara, S., Nakao, M., et al. (2006). Involvement of SUMO modification in MBD1-and MCAF1-mediated heterochromatin formation. J. Biol. Chem. 281, 23180-23190. doi: 10.1074/jbc. M602280200
253. Unoki, M., Nishidate, T., and Nakamura, Y. (2004). ICBP90, an E2F-1 target, recruits HDAC1 and binds to methyl-CpG through its SRA domain. Oncogene 23, 7601-7610. doi: 10.1038/sj.onc.1208053
254. Vella, P., Scelfo, A., Jammula, S., Chiacchiera, F., Williams, K., Cuomo, A., et al. (2013). Tet proteins connect the O-Linked N-acetylglucosamine transferase Ogt to chromatin in embryonic stem cells. Mol. Cell 49, 645-656. doi: 10.1016/j.molcel.2012.12.019
255. Vincent, J. J., Huang, Y., Chen, P.-Y., Feng, S., Calvopiña, J. H., Nee, K., et al. (2013). Stage-specific roles for Tet1 and Tet2 in DNA demethylation in primordial germ cells. Cell Stem Cell 12, 470-478. doi: 10.1016/j.stem.2013.01.016
256. Wade, P. A., Gegonne, A., Jones, P. L., Ballestar, E., Aubry, F., and Wolffe, A. P. (1999). Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation. Nat. Genet. 23, 62-66. doi: 10.1038/12664
257. Wakefield, R. I., Smith, B. O., Nan, X., Free, A., Soteriou, A., Uhrin, D., et al. (1999). The solution structure of the domain from MeCP2 that binds to methylated DNA. J. Mol. Biol. 291, 1055-1065. doi: 10.1006/jmbi.1999.3023
258. Walter, M. J., Ding, L., Shen, D., Shao, J., Grillot, M., McLellan, M., et al. (2011). Recurrent DNMT3A mutations in patients with myelodysplastic syndromes. Leukemia 25, 1153-1158. doi: 10.1038/leu.2011.44
259. Wang, C., Shen, J., Yang, Z., Chen, P., Zhao, B., Hu, W., et al. (2011). Structural basis for site-specific reading of unmodified R2 of histone H3 tail by UHRF1 PHD finger. Cell Res. 21, 1379-1382. doi: 10.1038/cr.2011.123
260. Watanabe, D., Suetake, I., Tada, T., and Tajima, S. (2002). Stage-and cell-specific expression of Dnmt3a and Dnmt3b during embryogenesis. Mech. Dev. 118, 187-190. doi: 10.1016/S0925-4773(02)00242-3
261. Watanabe, D., Suetake, I., Tajima, S., and Hanaoka, K. (2004). Expression of Dnmt3b in mouse hematopoietic progenitor cells and spermatogonia at specific stages. Gene Expr. Patterns 5, 43-49. doi: 10.1016/j.modgep.2004.06.008
262. Weber, A., Marquardt, J., Elzi, D., Forster, N., Starke, S., Glaum, A., et al. (2008). Zbtb4 represses transcription of P21CIP1 and controls the cellular response to p53 activation. EMBO J. 27, 1563-1574. doi: 10.1038/emboj.2008.85
263. Welling, M., Chen, H.-H., Muñoz, J., Musheev, M. U., Kester, L., Junker, J. P., et al. (2015). DAZL regulates Tet 1 translation in murine embryonic stem cells. EMBO Rep. 16, 791-802. doi: 10.15252/embr.201540538
264. Whyte, W. A., Bilodeau, S., Orlando, D. A., Hoke, H. A., Frampton, G. M., Foster, C. T., et al. (2012). Enhancer decommissioning by LSD1 during embryonic stem cell differentiation. Nature 482, 221-225. doi: 10.1038/nature10805
265. Williams, K., Christensen, J., Pedersen, M. T., Johansen, J. V., Cloos, P. A., Rappsilber, J., et al. (2011). TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity. Nature 473, 343-348. doi: 10.1038/nature10066
266. Winkelmann, J., Lin, L., Schormair, B., Kornum, B. R., Faraco, J., Plazzi, G., et al. (2012). Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy. Hum. Mol. Genet. 21, 2205-2210. doi: 10.1093/hmg/dds035
267. Woo, H. R., Pontes, O., Pikaard, C. S., and Richards, E. J. (2007). VIM1, a methylcytosine-binding protein required for centromeric heterochromatinization. Genes Dev. 21, 267-277. doi: 10.1101/gad.1512007
268. Woodcock, C. L. (2006). Chromatin architecture. Curr. Opin. Struct. Biol. 16, 213-220. doi: 10.1016/j.sbi.2006.02.005
269. Wossidlo, M., Nakamura, T., Lepikhov, K., Marques, C. J., Zakhartchenko, V., Boiani, M., et al. (2011). 5-Hydroxymethylcytosine in the mammalian zygote is linked with epigenetic reprogramming. Nat. Commun. 2:241. doi: 10.1038/ncomms1240
270. Xie, Z. H., Huang, Y. N., Chen, Z. X., Riggs, A. D., Ding, J. P., Gowher, H., et al. (2006). Mutations in DNA methyltransferase DNMT3B in ICF syndrome affect its regulation by DNMT3L. Hum. Mol. Genet. 15, 1375-1385. doi: 10.1093/hmg/ddl059
271. Xu, G. L., Bestor, T. H., Bourc'His, D., Hsieh, C. L., Tommerup, N., Bugge, M., et al. (1999). Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature 402, 187-191. doi: 10.1038/46052
272. Xu, W., Yang, H., Liu, Y., Yang, Y., Wang, P., Kim, S. H., et al. (2011). Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of a-ketoglutarate-dependent dioxygenases. Cancer Cell 19, 17-30. doi: 10.1016/j.ccr.2010.12.014
273. Xu, Y., Wu, F., Tan, L., Kong, L., Xiong, L., Deng, J., et al. (2011). Genome-wide regulation of 5hmC, 5mC, and gene expression by Tet1 hydroxylase in mouse embryonic stem cells. Mol. Cell 42, 451-464. doi: 10.1016/j.molcel.2011.04.005
274. Xu, Y., Xu, C., Kato, A., Tempel, W., Abreu, J. G., Bian, C., et al. (2012). Tet3 CXXC domain and dioxygenase activity cooperatively regulate key genes for xenopus eye and neural development. Cell 151, 1200-1213. doi: 10.1016/j.cell.2012.11.014
275. Yamaguchi, S., Hong, K., Liu, R., Shen, L., Inoue, A., Diep, D., et al. (2012). Tet1 controls meiosis by regulating meiotic gene expression. Nature 492, 443-447. doi: 10.1038/nature11709
276. Yamaguchi, S., Shen, L., Liu, Y., Sendler, D., and Zhang, Y. (2013). Role of Tet1 in erasure of genomic imprinting. Nature 504, 460-464. doi: 10.1038/nature12805
277. Yasui, D. H., Peddada, S., Bieda, M. C., Vallero, R. O., Hogart, A., Nagarajan, R. P., et al. (2007). Integrated epigenomic analyses of neuronal MeCP2 reveal a role for long-range interaction with active genes. Proc. Natl. Acad. Sci. U.S.A. 104, 19416-19421. doi: 10.1073/pnas.0707442104
278. Yildirim, O., Li, R., Hung, J. H., Chen, P. B., Dong, X., Ee, L. S., et al. (2011). Mbd3/NURD complex regulates expression of 5-hydroxymethylcytosine marked genes in embryonic stem cells. Cell 147, 1498-1510. doi: 10.1016/j.cell.2011.11.054
279. Yoder, J. A., and Bestor, T. H. (1998). A candidate mammalian DNA methyltransferase related to pmt1p of fission yeast. Hum. Mol. Genet. 7, 279-284. doi: 10.1093/hmg/7.2.279
280. Yoder, J. A., Yen, R. W., Vertino, P. M., Bestor, T. H., and Baylin, S. B. (1996). New 5' regions of the murine and human genes for DNA (cytosine-5)-methyltransferase. J. Biol. Chem. 271, 31092-31097. doi: 10.1074/jbc.271.49.31092
281. Yoon, H. G., Chan, D. W., Reynolds, A. B., Qin, J., and Wong, J. (2003). N-CoR mediates DNA methylation-dependent repression through a methyl CpG binding protein Kaiso. Mol. Cell 12, 723-734. doi: 10.1016/j.molcel.2003.08.008
282. Yu, C., Zhang, Y. L., Pan, W. W., Li, X. M., Wang, Z. W., Ge, Z. J., et al. (2013). CRL4 complex regulates mammalian oocyte survival and reprogramming by activation of TET proteins. Science 342, 1518-1521. doi: 10.1126/science.1244587
283. Zhang, H., Zhang, X., Clark, E., Mulcahey, M., Huang, S., and Shi, Y. G. (2010). TET1 is a DNA-binding protein that modulates DNA methylation and gene transcription via hydroxylation of 5-methylcytosine. Cell Res. 20, 1390-1393. doi: 10.1038/cr.2010.156
284. Zhang, J., Gao, Q., Li, P., Liu, X., Jia, Y., Wu, W., et al. (2011). S phase-dependent interaction with DNMT1 dictates the role of UHRF1 but not UHRF2 in DNA methylation maintenance. Cell Res. 21, 1723-1739. doi: 10.1038/cr.2011.176
285. Zhang, P., Su, L., Wang, Z., Zhang, S., Guan, J., Chen, Y., et al. (2012). The involvement of 5-hydroxymethylcytosine in Active DNA demethylation in Mice. Biol. Reprod. 86, 104. doi: 10.1095/biolreprod.111.096073
286. Zhang, Q., Liu, X., Gao, W., Li, P., Hou, J., Li, J., et al. (2014). Differential regulation of the ten-eleven translocation (TET) family of dioxygenases by O-linked beta-N-acetylglucosamine transferase (OGT). J. Biol. Chem. 289, 5986-5996. doi: 10.1074/jbc. M113.524140
287. Zhang, R. R., Cui, Q. Y., Murai, K., Lim, Y. C., Smith, Z. D., Jin, S., et al. (2013). Tet1 regulates adult hippocampal neurogenesis and cognition. Cell Stem Cell 13, 237-245. doi: 10.1016/j.stem.2013.05.006
288. Zhang, Y., Ng, H. H., Erdjument-Bromage, H., Tempst, P., Bird, A., and Reinberg, D. (1999). Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation. Genes Dev. 13, 1924-1935.
289. Zhao, X., Ueba, T., Christie, B. R., Barkho, B., McConnell, M. J., Nakashima, K., et al. (2003). Mice lacking methyl-CpG binding protein 1 have deficits in adult neurogenesis and hippocampal function. Proc. Natl. Acad. Sci. U.S.A. 100, 6777-6782. doi: 10.1073/pnas.1131928100
290. Zhou, Z., Qin, J., Tang, J., Li, B., Geng, Q., Jiang, W., et al. (2013). Down-regulation of MeCP2 in Hirschsprung's disease. J. Pediatr. Surg. 48, 2099-2105. doi: 10.1016/j.jpedsurg.2013.07.011
291. Zocchi, L., and Sassone-Corsi, P. (2012). SIRT1-mediated deacetylation of MeCP2 contributes to BDNF expression. Epigenetics 7, 695-700. doi: 10.4161/epi.20733