TET Enzymes and 5hmC in Adaptive and Innate Immune Systems
Chan-Wang J Lio, Anjana Rao, Chan-Wang J Lio, Anjana Rao
Abstract
DNA methylation is an abundant and stable epigenetic modification that allows inheritance of information from parental to daughter cells. At active genomic regions, DNA methylation can be reversed by TET (Ten-eleven translocation) enzymes, which are responsible for fine-tuning methylation patterns. TET enzymes oxidize the methyl group of 5-methylcytosine (5mC) to yield 5-hydroxymethylcytosine (5hmC) and other oxidized methylcytosines, facilitating both passive and active demethylation. Increasing evidence has demonstrated the essential functions of TET enzymes in regulating gene expression, promoting cell differentiation, and suppressing tumor formation. In this review, we will focus on recent discoveries of the functions of TET enzymes in the development and function of lymphoid and myeloid cells. How TET activity can be modulated by metabolites, including vitamin C and 2-hydroxyglutarate, and its potential application in shaping the course of immune response will be discussed.
Keywords: 5 hydroxymethylcytosine; 5hmC; DNA modification; epigenetics (methylation/demethylation); gene regulation and expression; ten eleven translocation (TET).
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References
- Lister R, Pelizzola M., Dowen R.H., Hawkins R.D., Hon G., Tonti-Filippini J., et al. . (2009). Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462, 315–322. 10.1038/nature08514
- Lyko F. The DNA methyltransferase family: a versatile toolkit for epigenetic regulation. Nat Rev Genet. (2018) 19:81–92. 10.1038/nrg.2017.80
- Pastor WA, Aravind L, Rao A. TETonic shift: biological roles of TET proteins in DNA demethylation and transcription. Nat Rev Mol Cell Biol. (2013) 14:341–56. 10.1038/nrm3589
- WuX Zhang Y. TET-mediated active DNA demethylation: mechanism, function and beyond. Nat Rev Genet. (2017) 18:517–34. 10.1038/nrg.2017.33
- Xu C, Corces VG. Nascent DNA methylome mapping reveals inheritance of hemimethylation at CTCF/cohesin sites. Science (2018) 359:1166–70. 10.1126/science.aan5480
- Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, et al. . Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science (2009) 324:930–5. 10.1126/science.1170116
- Kriaucionis S, Heintz N. The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science (2009) 324:929–30. 10.1126/science.1169786
- Wyatt GR, Cohen SS. The bases of the nucleic acids of some bacterial and animal viruses: the occurrence of 5-hydroxymethylcytosine. Biochem J. (1953) 55:774–82. 10.1042/bj0550774
- Iyer LM, Abhiman S, de Souza RF, Aravind L. Origin and evolution of peptide-modifying dioxygenases and identification of the wybutosine hydroxylase/hydroperoxidase. Nucleic Acids Res. (2010) 38:5261–79. 10.1093/nar/gkq265
- Iyer LM, 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 (2009) 8:1698–710. 10.4161/cc.8.11.8580
- Moroz LL, Kocot KM, Citarella MR, Dosung S, Norekian TP, Povolotskaya IS, et al. . The ctenophore genome and the evolutionary origins of neural systems. Nature (2014) 510:109–14. 10.1038/nature13400
- Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA, et al. . Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science (2011) 333:1300–3. 10.1126/science.1210597
- Dalton SR, Bellacosa A. DNA demethylation by TDG. Epigenomics (2012) 4:459–67. 10.2217/epi.12.36
- Kohli RM, Zhang Y. TET enzymes, TDG and the dynamics of DNA demethylation. Nature (2013) 502:472–9. 10.1038/nature12750
- Otani J, Kimura H, Sharif J, Endo TA, Mishima Y, Kawakami T, et al. . Cell cycle-dependent turnover of 5-hydroxymethyl cytosine in mouse embryonic stem cells. PLoS ONE (2013) 8:e82961. 10.1371/journal.pone.0082961
- Hon GC, Song CX, Du T, Jin F, Selvaraj S, Lee AY, et al. . 5mC oxidation by Tet2 modulates enhancer activity and timing of transcriptome reprogramming during differentiation. Mol Cell (2014) 56:286–97. 10.1016/j.molcel.2014.08.026
- Huang Y, Chavez L, Chang X, Wang X, Pastor WA, Kang J, et al. . Distinct roles of the methylcytosine oxidases Tet1 and Tet2 in mouse embryonic stem cells. Proc Nat Acad Sci USA. (2014) 111:1361–6. 10.1073/pnas.1322921111
- Tsagaratou A, Aijo T, Lio CW, Yue X, Huang Y, Jacobsen SE, et al. . Dissecting the dynamic changes of 5-hydroxymethylcytosine in T-cell development and differentiation. Proc Nat Acad Sci USA. (2014) 111:E3306–3315. 10.1073/pnas.1412327111
- Costa Y, Ding J, Theunissen TW, Faiola F, Hore TA, Shliaha PV, et al. . NANOG-dependent function of TET1 and TET2 in establishment of pluripotency. Nature (2013) 495:370–4. 10.1038/nature11925
- de la Rica L, Rodriguez-Ubreva J, Garcia M, Islam AB, Urquiza JM, Hernando H, et al. . PU.1 target genes undergo Tet2-coupled demethylation and DNMT3b-mediated methylation in monocyte-to-osteoclast differentiation. Genome Biol. (2013) 14:R99. 10.1186/gb-2013-14-9-r99
- Guilhamon P, Eskandarpour M, Halai D, Wilson GA, Feber A, Teschendorff AE, et al. . Meta-analysis of IDH-mutant cancers identifies EBF1 as an interaction partner for TET2. Nat Commun. (2013) 4:2166. 10.1038/ncomms3166
- Lio CJ, Zhang J, Gonzalez-Avalos E, Hogan PG, Chang X, Rao A. Tet2 and Tet3 cooperate with B-lineage transcription factors to regulate DNA modification and chromatin accessibility. Elife (2016) 5:e18290. 10.7554/eLife.18290
- Wang Y, Xiao M, Chen X, Chen L, Xu Y, Lv L, et al. . WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell proliferation. Mol Cell (2015) 57:662–73. 10.1016/j.molcel.2014.12.023
- Xiong J, Zhang Z, Chen J, Huang H, Xu Y, Ding X, et al. . Cooperative action between SALL4A and TET proteins in stepwise oxidation of 5-methylcytosine. Mol Cell (2016) 64:913–25. 10.1016/j.molcel.2016.10.013
- An J, Gonzalez-Avalos E, Chawla A, Jeong M, Lopez-Moyado IF, Li W, et al. . Acute loss of TET function results in aggressive myeloid cancer in mice. Nat Commun. (2015) 6:10071. 10.1038/ncomms10071
- Ko M, An J, Pastor WA, Koralov SB, Rajewsky K, Rao A. TET proteins and 5-methylcytosine oxidation in hematological cancers. Immunol Rev. (2015) 263:6–21. 10.1111/imr.12239
- Li X, Yue X, Pastor WA, Lin L, Georges R, Chavez L, et al. . Tet proteins influence the balance between neuroectodermal and mesodermal fate choice by inhibiting Wnt signaling. Proc Nat Acad Sci USA. (2016) 113:E8267–76. 10.1073/pnas.1617802113
- Lio C-WJ, Shukla V, Samaniego-Castruita D, González-Avalos E, Chakraborty A, Yue X, et al. TET enzymes augment AID expression via 5hmC modifications at the Aicda superenhancer (2018). bioRxiv. 10.1101/438531
- Madzo J, Liu H, Rodriguez A, Vasanthakumar A, Sundaravel S, Caces DBD, et al. . Hydroxymethylation at gene regulatory regions directs stem/early progenitor cell commitment during erythropoiesis. Cell Rep. (2014) 6:231–44. 10.1016/j.celrep.2013.11.044
- Santiago M, Antunes C, Guedes M, Sousa N, Marques CJ. TET enzymes and DNA hydroxymethylation in neural development and function—How critical are they? Genomics (2014) 104:334–40. 10.1016/j.ygeno.2014.08.018
- Huang Y, Rao A. Connections between TET proteins and aberrant DNA modification in cancer. Trends Genet. (2014) 30:464–74. 10.1016/j.tig.2014.07.005
- Ko M, An J, Rao A. DNA methylation and hydroxymethylation in hematologic differentiation and transformation. Curr Opin Cell Biol. (2015) 37:91–101. 10.1016/j.ceb.2015.10.009
- Tsagaratou A, Gonzalez-Avalos E, Rautio S, Scott-Browne JP, Togher S, Pastor WA, et al. . TET proteins regulate the lineage specification and TCR-mediated expansion of iNKT cells. Nat Immunol. (2016) 18:45–53. 10.1038/ni.3630
- Bowman RL, Levine RL. TET2 in normal and malignant hematopoiesis. Cold Spring Harb Perspect Med. (2017) 7:a026518. 10.1101/cshperspect.a026518.
- Rasmussen KD, Helin K. Role of TET enzymes in DNA methylation, development, and cancer. Genes Dev. (2016) 30:733–50. 10.1101/gad.276568.115
- Shih AH, Abdel-Wahab O, Patel JP, Levine RL. The role of mutations in epigenetic regulators in myeloid malignancies. Nat Rev Cancer (2012) 12:599–612. 10.1038/nrc3343
- Orlanski S, Labi V, Reizel Y, Spiro A, Lichtenstein M, Levin-Klein R, et al. . Tissue-specific DNA demethylation is required for proper B-cell differentiation and function. Proc Nat Acad Sci USA. (2016) 113:5018–23. 10.1073/pnas.1604365113
- Dominguez PM, Ghamlouch H, Rosikiewicz W, Kumar P, Beguelin W, Fontan L, et al. . TET2 deficiency causes germinal center hyperplasia, impairs plasma cell differentiation, and promotes B-cell lymphomagenesis. Cancer Dis. (2018) 8:1632–53. 10.1158/-18-0657
- Yue X, Trifari S, Aijo T, Tsagaratou A, Pastor WA, Zepeda-Martinez JA, et al. . Control of Foxp3 stability through modulation of TET activity. J Exp Med. (2016) 213:377–97. 10.1084/jem.20151438
- Yang R, Qu C, Zhou Y, Konkel JE, Shi S, Liu Y, et al. . Hydrogen sulfide promotes Tet1- and Tet2-mediated Foxp3 demethylation to drive regulatory T cell differentiation and maintain immune homeostasis. Immunity (2015) 43:251–63. 10.1016/j.immuni.2015.07.017
- Ichiyama K, Chen T, Wang X, Yan X, Kim BS, Tanaka S, et al. . The methylcytosine dioxygenase Tet2 promotes DNA demethylation and activation of cytokine gene expression in T cells. Immunity (2015) 42:613–26. 10.1016/j.immuni.2015.03.005
- Carty SA, Gohil M, Banks LB, Cotton RM, Johnson ME, Stelekati E, et al. . The loss of TET2 promotes CD8+ T cell memory differentiation. J Immunol. (2017) 200:82–91. 10.4049/jimmunol.1700559
- Montagner S, Leoni C, Emming S, Della Chiara G, Balestrieri C, Barozzi I, et al. . TET2 regulates mast cell differentiation and proliferation through catalytic and non-catalytic activities. Cell Rep. (2016) 15:1566–79. 10.1016/j.celrep.2016.04.044
- Shen Q, Zhang Q, Shi Y, Shi Q, Jiang Y, Gu Y, et al. . Tet2 promotes pathogen infection-induced myelopoiesis through mRNA oxidation. Nature (2018) 554:123–7. 10.1038/nature25434
- Cull AH, Snetsinger B, Buckstein R, Wells RA, Rauh MJ. Tet2 restrains inflammatory gene expression in macrophages. Exp Hematol. (2017) 55:56–70.e13. 10.1016/j.exphem.2017.08.001
- Zhang Q, Zhao K, Shen Q, Han Y, Gu Y, Li X, et al. . Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6. Nature (2015) 525:389–93. 10.1038/nature15252
- Fuster JJ, MacLauchlan S, Zuriaga MA, Polackal MN, Ostriker AC, Chakraborty R, et al. . Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science (2017) 355:842–7. 10.1126/science.aag1381
- Neves-Costa A, Moita LF. TET1 is a negative transcriptional regulator of IL-1beta in the THP-1 cell line. Mol Immunol. (2013) 54:264–70. 10.1016/j.molimm.2012.12.014
- Ma S, Wan X, Deng Z, Shi L, Hao C, Zhou Z, et al. . Epigenetic regulator CXXC5 recruits DNA demethylase Tet2 to regulate TLR7/9-elicited IFN response in pDCs. J Exp Med. (2017) 214:1471–91. 10.1084/jem.20161149
- Hahn MA, Qiu R, Wu X, Li AX, Zhang H, Wang J, et al. . Dynamics of 5-hydroxymethylcytosine and chromatin marks in Mammalian neurogenesis. Cell Rep. (2013) 3:291–300. 10.1016/j.celrep.2013.01.011
- Wu H, D'Alessio AC, Ito S, Wang Z, Cui K, Zhao K, et al. . Genome-wide analysis of 5-hydroxymethylcytosine distribution reveals its dual function in transcriptional regulation in mouse embryonic stem cells. Genes Dev. (2011) 25:679–84. 10.1101/gad.2036011
- Stroud H, Feng S, Morey Kinney S, Pradhan S, Jacobsen SE. 5-Hydroxymethylcytosine is associated with enhancers and gene bodies in human embryonic stem cells. Genome Biol. (2011) 12:R54. 10.1186/gb-2011-12-6-r54
- Du Q, Luu P-L, Stirzaker C, Clark SJ. Methyl-CpG-binding domain proteins: readers of the epigenome. Epigenomics (2015) 7:1051–73. 10.2217/epi.15.39
- Zhu H, Wang G, Qian J. Transcription factors as readers and effectors of DNA methylation. Nat Rev Genet. (2016) 17:551–65. 10.1038/nrg.2016.83
- Kulis M, Merkel A, Heath S, Queiros AC, Schuyler RP, Castellano G, et al. . Whole-genome fingerprint of the DNA methylome during human B cell differentiation. Nat Genet. (2015) 47:746–56. 10.1038/ng.3291
- Asmar F, Punj V, Christensen J, Pedersen MT, Pedersen A, Nielsen AB, et al. . Genome-wide profiling identifies a DNA methylation signature that associates with TET2 mutations in diffuse large B-cell lymphoma. Haematologica (2013) 98:1912–20. 10.3324/haematol.2013.088740
- Reddy A, Zhang J, Davis NS, Moffitt AB, Love CL, Waldrop A, et al. . Genetic and functional drivers of diffuse large B cell lymphoma. Cell (2017) 171:481–94.e15. 10.1016/j.cell.2017.09.027
- Schmitz R, Wright GW, Huang DW, Johnson CA, Phelan JD, Wang JQ, et al. . Genetics and pathogenesis of diffuse large B-cell lymphoma. N Engl J Med. (2018) 378:1396–407. 10.1056/NEJMoa1801445
- Sernandez IV, de Yebenes VG, Dorsett Y, Ramiro AR. Haploinsufficiency of activation-induced deaminase for antibody diversification and chromosome translocations both in vitro and in vivo. PLoS ONE (2008) 3:e3927. 10.1371/journal.pone.0003927
- Takizawa M, Tolarova H, Li Z, Dubois W, Lim S, Callen E, et al. . AID expression levels determine the extent of cMyc oncogenic translocations and the incidence of B cell tumor development. J Exp Med. (2008) 205:1949–57. 10.1084/jem.20081007
- Qian J, Wang Q, Dose M, Pruett N, Kieffer-Kwon K-R, Resch W, et al. . B cell super-enhancers and regulatory clusters recruit aid tumorigenic activity. Cell (2014) 159:1524–37. 10.1016/j.cell.2014.11.013
- Ko M, Bandukwala HS, An J, Lamperti ED, Thompson EC, Hastie R, et al. . Ten-eleven-translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice. Proc Nat Acad Sci USA. (2011) 108:14566–71. 10.1073/pnas.1112317108
- Lee YJ, Holzapfel KL, Zhu J, Jameson SC, Hogquist KA. Steady-state production of IL-4 modulates immunity in mouse strains and is determined by lineage diversity of iNKT cells. Nat Immunol. (2013) 14:1146–54. 10.1038/ni.2731
- Zheng Y, Josefowicz S, Chaudhry A, Peng XP, Forbush K, Rudensky AY. Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature (2010) 463:808–12. 10.1038/nature08750
- Someya K, Nakatsukasa H, Ito M, Kondo T, Tateda KI, Akanuma T, et al. . Improvement of Foxp3 stability through CNS2 demethylation by TET enzyme induction and activation. Int Immunol. (2017) 29:365–75. 10.1093/intimm/dxx049
- Wang L, Liu Y, Han R, Beier UH, Thomas RM, Wells AD, et al. . Mbd2 promotes foxp3 demethylation and T-regulatory-cell function. Mol Cell Biol. (2013) 33:4106–15. 10.1128/MCB.00144-13
- Wakamatsu E, Omori H, Kawano A, Ogawa S, Abe R. Strong TCR stimulation promotes the stabilization of Foxp3 expression in regulatory T cells induced in vitro through increasing the demethylation of Foxp3 CNS2. Biochem Biophy Res Commun. (2018) 503:2597–602. 10.1016/j.bbrc.2018.07.021
- Blaschke K, Ebata KT, Karimi MM, Zepeda-Martinez JA, Goyal P, Mahapatra S, et al. . Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. Nature (2013) 500:222–6. 10.1038/nature12362
- Sasidharan Nair V, Song MH, Oh KI. Vitamin C facilitates demethylation of the Foxp3 enhancer in a tet-dependent manner. J Immunol. (2016) 196:2119–31. 10.4049/jimmunol.1502352
- Dang L, Su S-SM. Isocitrate dehydrogenase mutation and (R)-2-hydroxyglutarate: from basic discovery to therapeutics development. Ann Rev Biochem. (2017) 86:305–31. 10.1146/annurev-biochem-061516-044732
- Ye D, Guan KL, Xiong Y. Metabolism, activity, and targeting of D- and L-2-hydroxyglutarates. Trends Cancer (2018) 4:151–65. 10.1016/j.trecan.2017.12.005
- Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, et al. . Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell (2011) 19:17–30. 10.1016/j.ccr.2010.12.014
- Xu T, Stewart KM, Wang X, Liu K, Xie M, Ryu JK, et al. . Metabolic control of TH17 and induced Treg cell balance by an epigenetic mechanism. Nature (2017) 548:228–33. 10.1038/nature23475
- Nestor CE, Lentini A, Hagg Nilsson C, Gawel DR, Gustafsson M, Mattson L, et al. . 5-Hydroxymethylcytosine remodeling precedes lineage specification during differentiation of human CD4(+) T Cells. Cell Rep. (2016) 16:559–70. 10.1016/j.celrep.2016.05.091
- Tyrakis PA, Palazon A, Macias D, Lee KL, Phan AT, Velica P, et al. . S-2-hydroxyglutarate regulates CD8(+) T-lymphocyte fate. Nature (2016) 540:236–41. 10.1038/nature20165
- Fraietta JA, Nobles CL, Sammons MA, Lundh S, Carty SA, Reich TJ, et al. . Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature (2018) 558:307–12. 10.1038/s41586-018-0178-z
- Pronier E, Almire C, Mokrani H, Vasanthakumar A, Simon A, da Costa Reis Monte Mor B, et al. . Inhibition of TET2-mediated conversion of 5-methylcytosine to 5-hydroxymethylcytosine disturbs erythroid and granulomonocytic differentiation of human hematopoietic progenitors. Blood (2011) 118:2551–5. 10.1182/blood-2010-12-324707
- Alvarez-Errico D, Vento-Tormo R, Sieweke M, Ballestar E. Epigenetic control of myeloid cell differentiation, identity and function. Nat Rev Immunol. (2015) 15:7–17. 10.1038/nri3777
- Klug M, Heinz S, Gebhard C, Schwarzfischer L, Krause SW, Andreesen R, et al. Active DNA demethylation in human postmitotic cells correlates with activating histone modifications, but not transcription levels. Genome Biol. (2010) 11:R63 10.1186/gb-2010-11-6-r63
- Klug M, Schmidhofer S, Gebhard C, Andreesen R, Rehli M. 5-Hydroxymethylcytosine is an essential intermediate of active DNA demethylation processes in primary human monocytes. Genome Biol. (2013) 14:R46. 10.1186/gb-2013-14-5-r46
- Vento-Tormo R, Company C, Rodriguez-Ubreva J, de la Rica L, Urquiza JM, Javierre BM, et al. . IL-4 orchestrates STAT6-mediated DNA demethylation leading to dendritic cell differentiation. Genome Biol. (2016) 17:4. 10.1186/s13059-015-0863-2
- Wiles ET, Selker EU. H3K27 methylation: a promiscuous repressive chromatin mark. Curr Opin Genet Dev. (2017) 43:31–7. 10.1016/j.gde.2016.11.001
- Garcia-Gomez A, Li T, Kerick M, Catala-Moll F, Comet NR, Rodriguez-Ubreva J, et al. . TET2- and TDG-mediated changes are required for the acquisition of distinct histone modifications in divergent terminal differentiation of myeloid cells. Nucleic Acids Res. (2017) 45:10002–17. 10.1093/nar/gkx666
- Pan W, Zhu S, Qu K, Meeth K, Cheng J, He K, et al. . The DNA methylcytosine dioxygenase Tet2 sustains immunosuppressive function of tumor-infiltrating myeloid cells to promote melanoma progression. Immunity (2017) 47:284–97.e5. 10.1016/j.immuni.2017.07.020
- Scott DL, Wolfe F, Huizinga TWJ. Rheumatoid arthritis. Lancet (2010) 376:1094–108. 10.1016/S0140-6736(10)60826-4
- Delatte B, Wang F, Ngoc LV, Collignon E, Bonvin E, Deplus R, et al. . RNA biochemistry. Transcriptome-wide distribution and function of RNA hydroxymethylcytosine. Science (2016) 351:282–5. 10.1126/science.aac5253
- Guallar D, Bi X, Pardavila JA, Huang X, Saenz C, Shi X, et al. . RNA-dependent chromatin targeting of TET2 for endogenous retrovirus control in pluripotent stem cells. Nat Genet. (2018) 50:443–51. 10.1038/s41588-018-0060-9
- Meisel M, Hinterleitner R, Pacis A, Chen L, Earley ZM, Mayassi T, et al. . Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host. Nature (2018) 557:580–4. 10.1038/s41586-018-0125-z
- Lai AY, Fatemi M, Dhasarathy A, Malone C, Sobol SE, Geigerman C, et al. . DNA methylation prevents CTCF-mediated silencing of the oncogene BCL6 in B cell lymphomas. J Exp Med. (2010) 207:1939–50. 10.1084/jem.20100204
- Dyson HJ, Wright PE. Role of intrinsic protein disorder in the function and interactions of the transcriptional coactivators CREB-binding Protein (CBP) and p300. J Biol Chem. (2016) 291:6714–22. 10.1074/jbc.R115.692020
- Chodavarapu RK, Feng S, Bernatavichute YV, Chen PY, Stroud H, Yu Y, et al. . Relationship between nucleosome positioning and DNA methylation. Nature (2010) 466:388–92. 10.1038/nature09147
- Choy JS, Wei S, Lee JY, Tan S, Chu S, Lee T-H. DNA methylation increases nucleosome compaction and rigidity. J Am Chem Soc. (2010) 132:1782–3. 10.1021/ja910264z
- Yin Y, Morgunova E, Jolma A, Kaasinen E, Sahu B, Khund-Sayeed S, et al. . Impact of cytosine methylation on DNA binding specificities of human transcription factors. Science (2017) 356:eaaj2239. 10.1126/science.aaj2239
- Hashimoto H, Olanrewaju YO, Zheng Y, Wilson GG, Zhang X, Cheng X. Wilms tumor protein recognizes 5-carboxylcytosine within a specific DNA sequence. Genes Dev. (2014) 28:2304–13. 10.1101/gad.250746.114
- Crawford DJ, Liu MY, Nabel CS, Cao X-J, Garcia BA, Kohli RM. Tet2 catalyzes stepwise 5-methylcytosine oxidation by an iterative and de novo mechanism. J Am Chem Soc. (2016) 138:730–3. 10.1021/jacs.5b10554
- Bachman M, Uribe-Lewis S, Yang X, Burgess HE, Iurlaro M, Reik W, et al. . 5-formylcytosine can be a stable DNA modification in mammals. Nat Chem Biol. (2015) 11:555–7. 10.1038/nchembio.1848
- Bachman M, Uribe-Lewis S, Yang X, Williams M, Murrell A, Balasubramanian S. 5-Hydroxymethylcytosine is a predominantly stable DNA modification. Nature chemistry (2014) 6:1049–55. 10.1038/nchem.2064
- Flavahan WA, Drier Y, Liau BB, Gillespie SM, Venteicher AS, Stemmer-Rachamimov AO, et al. . Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature (2016) 529:110–4. 10.1038/nature16490
- Hashimoto H, Wang D, Horton JR, Zhang X, Corces VG, Cheng X. Structural basis for the versatile and methylation-dependent binding of CTCF to DNA. Mol Cell (2017) 66:711–20.e3. 10.1016/j.molcel.2017.05.004
- Deplus R, Delatte B, Schwinn MK, Defrance M, Méndez J, Murphy N, et al. . TET2 and TET3 regulate GlcNAcylation and H3K4 methylation through OGT and SET1/COMPASS. EMBO J. (2013) 32:645–55.
- Baubec T, Colombo DF, Wirbelauer C, Schmidt J, Burger L, Krebs AR, et al. . Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation. Nature (2015) 520:243–7. 10.1038/nature14176
- Dhayalan A, Rajavelu A, Rathert P, Tamas R, Jurkowska RZ, Ragozin S, et al. . The Dnmt3a PWWP domain reads histone 3 lysine 36 trimethylation and guides DNA methylation. J Biol Chem. (2010) 285:26114–20. 10.1074/jbc.M109.089433
- Morselli M, Pastor WA, Montanini B, Nee K, Ferrari R, Fu K, et al. . In vivo targeting of de novo DNA methylation by histone modifications in yeast and mouse. Elife (2015) 4:e06205. 10.7554/eLife.06205
- Zhang YW, Wang Z, Xie W, Cai Y, Xia L, Easwaran H, et al. . Acetylation enhances TET2 function in protecting against abnormal DNA methylation during oxidative stress. Mol Cell (2017) 65:323–35. 10.1016/j.molcel.2016.12.013
- Cimmino L, Dolgalev I, Wang Y, Yoshimi A, Martin GH, Wang J, et al. . Restoration of TET2 function blocks aberrant self-renewal and leukemia progression. Cell (2017) 170:1079–1095.e20. 10.1016/j.cell.2017.07.032
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