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Structure and Function of TET Enzymes

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DNA Methyltransferases - Role and Function

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1389))

Abstract

Mammalian DNA methylation mainly occurs at the carbon-C5 position of cytosine (5mC). TET enzymes were discovered to successively oxidize 5mC to 5-hydromethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). Ten-eleven translocation (TET) enzymes and oxidized 5mC derivatives play important roles in various biological and pathological processes, including regulation of DNA demethylation, gene transcription, embryonic development, and oncogenesis. In this chapter, we will discuss the discovery of TET-mediated 5mC oxidation and the structure, function, and regulation of TET enzymes. We start with brief descriptions of the mechanisms of TET-mediated 5mC oxidation and TET-dependent DNA demethylation. We then discuss the TET-mediated epigenetic reprogramming in pluripotency maintenance and embryogenesis, as well as in tumorigenesis and neural system. We further describe the structural basis for substrate recognition and preference in TET-mediated 5mC oxidation. Finally, we summarize the chemical molecules and interacting proteins that regulate TET’s activity.

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Abbreviations

2HG:

2-Hydroxyglutarate

5caC:

5-Carboxylcytosine

5fC:

5-Formylcytosine

5hmC:

5-Hydromethylcytosine

5hmrC:

5-Hydroxymethylcytidine

5mC:

5-Methylcytosine

5mrC:

5-Methylcytidine

6mA:

N6-methyladenine

α-KG:

α-Ketoglutarate

ABH2:

AlkB homolog 2

AID:

Activation-induced deaminase

AML:

Acute myeloid leukemia

APOBEC:

Apolipoprotein B mRNA-editing enzyme complex

BER:

Base excision repair

CD:

Catalytic domain

Chip-seq:

Chromatin immunoprecipitation-sequencing

CMML:

Chronic myelomonocytic leukemia

CpG:

Cytosine-phosphate-guanine

CXXC:

Cysteine-X-X-cysteine

Cys-C:

Cys-rich C-terminal

Cys-N:

Cys-rich N-terminal

Cys-rich:

Cysteine rich

DMAD:

DNA 6mA demethylase

DNMT:

DNA methyltransferase

DSBH:

Double-stranded β-helix

E11.5:

Embryonic day 11.5

FH:

Fumarate hydratase

HCF1:

Host cell factor 1

HEK293:

Human embryonic kidney 293

hmU:

Hydroxymethyluracil

IDH:

Isocitrate dehydrogenase

iPSCs:

Induced pluripotent stem cells

JBP:

J-binding protein

JmjC:

Jumonji C

LC-MS:

Liquid chromatography-mass spectrometry

MEFs:

Mouse embryonic fibroblasts

mESCs:

Mouse embryonic stem cells

MET:

Mesenchymal-to-epithelial transition

NER:

Nucleotide excision repair

NOG:

N-oxalylglycine

OGT:

O-linked β-N-acetylglucosamine transferase

OSKM:

Oct4, Sox2, Klf4, and c-Myc

PGCs:

Primordial germ cells

Pol II:

RNA polymerase II

R-2HG:

R-2-hydroxyglutarate

SAM:

S-adenosyl methionine

SDH:

Succinate dehydrogenase

SMUG1:

Single-strand-selective monofunctional uracil DNA glycosylase 1

T7H:

Thymine-7-hydroxylase

TAB-seq:

Tet-assisted bisulfite sequencing

TCA:

Tricarboxylic acid

TDG:

Thymine-DNA glycosylase

TET:

Ten-eleven translocation

TSKM:

Tet1, Sox2, Klf4, and c-Myc

TSS:

Transcription start site

References

  • Abdel-Wahab O, Mullally A, Hedvat C, Garcia-Manero G, Patel J, Wadleigh M, Malinge S, Yao J, Kilpivaara O, Bhat R et al (2009) Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood 114:144–147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Agathocleous M, Meacham CE, Burgess RJ, Piskounova E, Zhao Z, Crane GM, Cowin BL, Bruner E, Murphy MM, Chen W et al (2017) Ascorbate regulates haematopoietic stem cell function and leukaemogenesis. Nature 549:476–481

    Article  PubMed  PubMed Central  Google Scholar 

  • Amouroux R, Nashun B, Shirane K, Nakagawa S, Hill PW, D’Souza Z, Nakayama M, Matsuda M, Turp A, Ndjetehe E et al (2016) De novo DNA methylation drives 5hmC accumulation in mouse zygotes. Nat Cell Biol 18:225–233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Antunes C, Sousa N, Pinto L, Marques CJ (2019) TET enzymes in neurophysiology and brain function. Neurosci Biobehav Rev 102:337–344

    Article  CAS  PubMed  Google Scholar 

  • Aravind L, Koonin EV (2001) The DNA-repair protein AlkB, EGL-9, and leprecan define new families of 2-oxoglutarate- and iron-dependent dioxygenases. Genome Biol 2:RESEARCH0007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Arioka Y, Watanabe A, Saito K, Yamada Y (2012) Activation-induced cytidine deaminase alters the subcellular localization of Tet family proteins. PLoS One 7:e45031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Basanta-Sanchez M, Wang R, Liu Z, Ye X, Li M, Shi X, Agris PF, Zhou Y, Huang Y, Sheng J (2017) TET1-Mediated Oxidation of 5-Formylcytosine (5fC) to 5-Carboxycytosine (5caC) in RNA. Chembiochem 18:72–76

    Article  CAS  PubMed  Google Scholar 

  • Bell E, Curry EW, Megchelenbrink W, Jouneau L, Brochard V, Tomaz RA, Mau KHT, Atlasi Y, de Souza RA, Marks H et al (2020) Dynamic CpG methylation delineates subregions within super-enhancers selectively decommissioned at the exit from naive pluripotency. Nat Commun 11:1112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bian K, Lenz SAP, Tang Q, Chen F, Qi R, Jost M, Drennan CL, Essigmann JM, Wetmore SD, Li D (2019) DNA repair enzymes ALKBH2, ALKBH3, and AlkB oxidize 5-methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxylcytosine in vitro. Nucleic Acids Res 47:5522–5529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bird A (2002) DNA methylation patterns and epigenetic memory. Genes Dev 16:6–21

    Article  CAS  PubMed  Google Scholar 

  • Blaschke K, Ebata KT, Karimi MM, Zepeda-Martinez JA, Goyal P, Mahapatra S, Tam A, Laird DJ, Hirst M, Rao A et al (2013) Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. Nature 500:222–226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Branco MR, Ficz G, Reik W (2011) Uncovering the role of 5-hydroxymethylcytosine in the epigenome. Nat Rev Genet 13:7–13

    Article  PubMed  Google Scholar 

  • Bruniquel D, Schwartz RH (2003) Selective, stable demethylation of the interleukin-2 gene enhances transcription by an active process. Nat Immunol 4:235–240

    Article  CAS  PubMed  Google Scholar 

  • Cai J, Chen L, Zhang Z, Zhang X, Lu X, Liu W, Shi G, Ge Y, Gao P, Yang Y et al (2019) Genome-wide mapping of 5-hydroxymethylcytosines in circulating cell-free DNA as a non-invasive approach for early detection of hepatocellular carcinoma. Gut 68:2195–2205

    Article  CAS  PubMed  Google Scholar 

  • Caldwell BA, Liu MY, Prasasya RD, Wang T, DeNizio JE, Leu NA, Amoh NYA, Krapp C, Lan Y, Shields EJ et al (2021) Functionally distinct roles for TET-oxidized 5-methylcytosine bases in somatic reprogramming to pluripotency. Mol Cell 81:859–869 e858

    Article  CAS  PubMed  Google Scholar 

  • Charlton J, Jung EJ, Mattei AL, Bailly N, Liao J, Martin EJ, Giesselmann P, Brandl B, Stamenova EK, Muller FJ et al (2020) TETs compete with DNMT3 activity in pluripotent cells at thousands of methylated somatic enhancers. Nat Genet 52:819-+

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen CC, Wang KY, Shen CK (2012) The mammalian de novo DNA methyltransferases DNMT3A and DNMT3B are also DNA 5-hydroxymethylcytosine dehydroxymethylases. J Biol Chem 287:33116–33121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen J, Guo L, Zhang L, Wu H, Yang J, Liu H, Wang X, Hu X, Gu T, Zhou Z et al (2013a) Vitamin C modulates TET1 function during somatic cell reprogramming. Nat Genet 45:1504–1509

    Article  CAS  PubMed  Google Scholar 

  • Chen Q, Chen Y, Bian C, Fujiki R, Yu X (2013b) TET2 promotes histone O-GlcNAcylation during gene transcription. Nature 493:561–564

    Article  CAS  PubMed  Google Scholar 

  • Ciccarone F, Valentini E, Zampieri M, Caiafa P (2015) 5mC-hydroxylase activity is influenced by the PARylation of TET1 enzyme. Oncotarget 6:24333–24347

    Article  PubMed  PubMed Central  Google Scholar 

  • Ciesielski P, JĂ³Åºwiak P, Forma E, KrzeÅ›lak A (2021) TET3- and OGT-dependent expression of genes involved in epithelial-mesenchymal transition in endometrial cancer. Int J Mol Sci 22

    Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cimmino L, Dolgalev I, Wang Y, Yoshimi A, Martin GH, Wang J, Ng V, Xia B, Witkowski MT, Mitchell-Flack M et al (2017) Restoration of TET2 function blocks aberrant self-renewal and leukemia progression. Cell 170:1079–1095 e1020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cliffe LJ, Kieft R, Southern T, Birkeland SR, Marshall M, Sweeney K, Sabatini R (2009) JBP1 and JBP2 are two distinct thymidine hydroxylases involved in J biosynthesis in genomic DNA of African trypanosomes. Nucleic Acids Res 37:1452–1462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cloos PA, Christensen J, Agger K, Maiolica A, Rappsilber J, Antal T, Hansen KH, Helin K (2006) The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3. Nature 442:307–311

    Article  CAS  PubMed  Google Scholar 

  • Costa Y, Ding J, Theunissen TW, Faiola F, Hore TA, Shliaha PV, Fidalgo M, Saunders A, Lawrence M, Dietmann S et al (2013) NANOG-dependent function of TET1 and TET2 in establishment of pluripotency. Nature 495:370–374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Crawford DJ, Liu MY, Nabel CS, Cao XJ, Garcia BA, Kohli RM (2016) Tet2 catalyzes stepwise 5-methylcytosine oxidation by an iterative and de novo mechanism. J Am Chem Soc 138:730–733

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dai HQ, Wang BA, Yang L, Chen JJ, Zhu GC, Sun ML, Ge H, Wang R, Chapman DL, Tang F et al (2016) TET-mediated DNA demethylation controls gastrulation by regulating Lefty-Nodal signalling. Nature 538:528–532

    Article  PubMed  Google Scholar 

  • Das AB, Kakadia PM, Wojcik D, Pemberton L, Browett PJ, Bohlander SK, Vissers MCM (2019) Clinical remission following ascorbate treatment in a case of acute myeloid leukemia with mutations in TET2 and WT1. Blood Cancer J 9:82

    Article  PubMed  PubMed Central  Google Scholar 

  • Das AB, Smith-Diaz CC, Vissers MCM (2021) Emerging epigenetic therapeutics for myeloid leukemia: modulating demethylase activity with ascorbate. Haematologica 106:14–25

    CAS  PubMed  Google Scholar 

  • Dawlaty MM, Ganz K, Powell BE, Hu YC, Markoulaki S, Cheng AW, Gao Q, Kim J, Choi SW, Page DC 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dawlaty MM, Breiling A, Le T, Raddatz G, Barrasa MI, Cheng AW, Gao Q, Powell BE, Li Z, Xu M et al (2013) Combined deficiency of Tet1 and Tet2 causes epigenetic abnormalities but is compatible with postnatal development. Dev Cell 24:310–323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • DeNizio JE, Liu MY, Leddin EM, Cisneros GA, Kohli RM (2019) Selectivity and promiscuity in TET-mediated oxidation of 5-methylcytosine in DNA and RNA. Biochemistry 58:411–421

    Article  CAS  PubMed  Google Scholar 

  • DeNizio JE, Dow BJ, Serrano JC, Ghanty U, Drohat AC, Kohli RM (2021) TET-TDG active DNA demethylation at CpG and Non-CpG sites. J Mol Biol 433:166877

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Deplus R, Delatte B, Schwinn MK, Defrance M, Mendez J, Murphy N, Dawson MA, Volkmar M, Putmans P, Calonne E et al (2013) TET2 and TET3 regulate GlcNAcylation and H3K4 methylation through OGT and SET1/COMPASS. EMBO J 32:645–655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dey AS, Bhattacharya C, Guan Y, Jha BK, Mukherji M (2021) Demethylation of non-CpG sites in DNA is initiated by TET2 5-methylcytosine dioxygenase. DNA 1:26–36

    Article  Google Scholar 

  • Diotel N, Merot Y, Coumailleau P, Gueguen MM, Serandour AA, Salbert G, Kah O (2017) 5-hydroxymethylcytosine marks postmitotic neural cells in the adult and developing vertebrate central nervous system. J Comp Neurol 525:478–497

    Article  CAS  PubMed  Google Scholar 

  • Doege CA, Inoue K, Yamashita T, Rhee DB, Travis S, Fujita R, Guarnieri P, Bhagat G, Vanti WB, Shih A et al (2012) Early-stage epigenetic modification during somatic cell reprogramming by Parp1 and Tet2. Nature 488:652–655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Englard S, Seifter S (1986) The biochemical functions of ascorbic acid. Annu Rev Nutr 6:365–406

    Article  CAS  PubMed  Google Scholar 

  • Esteban MA, Wang T, Qin B, Yang J, Qin D, Cai J, Li W, Weng Z, Chen J, Ni S et al (2010) Vitamin C enhances the generation of mouse and human induced pluripotent stem cells. Cell Stem Cell 6:71–79

    Article  CAS  PubMed  Google Scholar 

  • Feng Y, Chen JJ, Xie NB, Ding JH, You XJ, Tao WB, Zhang X, Yi C, Zhou X, Yuan BF et al (2021a) Direct decarboxylation of ten-eleven translocation-produced 5-carboxylcytosine in mammalian genomes forms a new mechanism for active DNA demethylation. Chem Sci 12:11322–11329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Feng Y, Xie N-B, Tao W-B, Ding J-H, You X-J, Ma C-J, Zhang X, Yi C, Zhou X, Yuan B-F et al (2021b) Transformation of 5-carboxylcytosine to cytosine through C–C bond cleavage in human cells constitutes a novel pathway for DNA demethylation. CCS Chem 3:994–1008

    Article  CAS  Google Scholar 

  • Ficz G, Branco MR, Seisenberger S, Santos F, Krueger F, Hore TA, Marques CJ, Andrews S, Reik W (2011) Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation. Nature 473:398–402

    Article  CAS  PubMed  Google Scholar 

  • Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A, Li Y, Bhagwat N, Vasanthakumar A, Fernandez HF et al (2010) Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18:553–567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Frauer C, Hoffmann T, Bultmann S, Casa V, Cardoso MC, Antes I, Leonhardt H (2011) Recognition of 5-hydroxymethylcytosine by the Uhrf1 SRA domain. PLoS One 6:e21306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fu L, Guerrero CR, Zhong N, Amato NJ, Liu Y, Liu S, Cai Q, Ji D, Jin SG, Niedernhofer LJ et al (2014) Tet-mediated formation of 5-hydroxymethylcytosine in RNA. J Am Chem Soc 136:11582–11585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fu Y, Luo GZ, Chen K, Deng X, Yu M, Han D, Hao Z, Liu J, Lu X, Dore LC et al (2015) N6-methyldeoxyadenosine marks active transcription start sites in Chlamydomonas. Cell 161:879–892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gao Y, Chen J, Li K, Wu T, Huang B, Liu W, Kou X, Zhang Y, Huang H, Jiang Y 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

    Article  CAS  PubMed  Google Scholar 

  • Gao L, Yang M, Wei Z, Gu M, Yang L, Bai C, Wu Y, Li G (2020) MSTN mutant promotes myogenic differentiation by increasing demethylase TET1 expression via the SMAD2/SMAD3 pathway. Int J Biol Sci 16:1324–1334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ghanty U, DeNizio JE, Liu MY, Kohli RM (2018) Exploiting substrate promiscuity to develop activity-based probes for ten-eleven translocation family enzymes. J Am Chem Soc 140:17329–17332

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ghanty U, Wang T, Kohli RM (2020) Nucleobase modifiers identify TET enzymes as bifunctional DNA dioxygenases capable of direct N-demethylation. Angew Chem Int Ed Engl 59:11312–11315

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ginno PA, Gaidatzis D, Feldmann A, Hoerner L, Imanci D, Burger L, Zilbermann F, Peters A, Edenhofer F, Smallwood SA et al (2020) A genome-scale map of DNA methylation turnover identifies site-specific dependencies of DNMT and TET activity. Nat Commun 11:2680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Globisch D, Munzel M, Muller M, Michalakis S, Wagner M, Koch S, Bruckl T, Biel M, Carell T (2010) Tissue distribution of 5-hydroxymethylcytosine and search for active demethylation intermediates. PLoS One 5:e15367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Greer EL, Blanco MA, Gu L, Sendinc E, Liu J, Aristizabal-Corrales D, Hsu CH, Aravind L, He C, Shi Y (2015) DNA methylation on N6-adenine in C. elegans. Cell 161:868–878

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gu TP, Guo F, Yang H, Wu HP, Xu GF, Liu W, Xie ZG, Shi L, He X, Jin SG et al (2011) The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes. Nature 477:606–610

    Article  CAS  PubMed  Google Scholar 

  • Guilhamon P, Eskandarpour M, Halai D, Wilson GA, Feber A, Teschendorff AE, Gomez V, Hergovich A, Tirabosco R, Fernanda Amary M et al (2013) Meta-analysis of IDH-mutant cancers identifies EBF1 as an interaction partner for TET2. Nat Commun 4:2166

    Article  PubMed  Google Scholar 

  • Guler GD, Ning Y, Ku CJ, Phillips T, McCarthy E, Ellison CK, Bergamaschi A, Collin F, Lloyd P, Scott A et al (2020) Detection of early stage pancreatic cancer using 5-hydroxymethylcytosine signatures in circulating cell free DNA. Nat Commun 11:5270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guo JU, Su Y, Zhong C, Ming GL, Song H (2011) Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell 145:423–434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guo F, Li X, Liang D, Li T, Zhu P, Guo H, Wu X, Wen L, Gu TP, Hu B et al (2014a) Active and passive demethylation of male and female pronuclear DNA in the mammalian zygote. Cell Stem Cell 15:447–459

    Article  CAS  PubMed  Google Scholar 

  • Guo JU, Su Y, Shin JH, Shin J, Li H, Xie B, Zhong C, Hu S, Le T, Fan G et al (2014b) Distribution, recognition and regulation of non-CpG methylation in the adult mammalian brain. Nat Neurosci 17:215–222

    Article  CAS  PubMed  Google Scholar 

  • Hackett JA, Sengupta R, Zylicz JJ, Murakami K, Lee C, Down TA, Surani MA (2013) Germline DNA demethylation dynamics and imprint erasure through 5-hydroxymethylcytosine. Science 339:448–452

    Article  CAS  PubMed  Google Scholar 

  • Haffner MC, Chaux A, Meeker AK, Esopi DM, Gerber J, Pellakuru LG, Toubaji A, Argani P, Iacobuzio-Donahue C, Nelson WG et al (2011) Global 5-hydroxymethylcytosine content is significantly reduced in tissue stem/progenitor cell compartments and in human cancers. Oncotarget 2:627–637

    Article  PubMed  PubMed Central  Google Scholar 

  • Hajkova P, Erhardt S, Lane N, Haaf T, El-Maarri O, Reik W, Walter J, Surani MA (2002) Epigenetic reprogramming in mouse primordial germ cells. Mech Dev 117:15–23

    Article  CAS  PubMed  Google Scholar 

  • Hamada S, Kim TD, Suzuki T, Itoh Y, Tsumoto H, Nakagawa H, Janknecht R, Miyata N (2009) Synthesis and activity of N-oxalylglycine and its derivatives as Jumonji C-domain-containing histone lysine demethylase inhibitors. Bioorg Med Chem Lett 19:2852–2855

    Article  CAS  PubMed  Google Scholar 

  • Hanover JA, Krause MW, Love DC (2012) Bittersweet memories: linking metabolism to epigenetics through O-GlcNAcylation. Nat Rev Mol Cell Biol 13:312–321

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hashimoto H, Pais JE, Zhang X, Saleh L, Fu ZQ, Dai N, Correa IR Jr, Zheng Y, Cheng X (2014) Structure of a Naegleria Tet-like dioxygenase in complex with 5-methylcytosine DNA. Nature 506:391–395

    Article  CAS  PubMed  Google Scholar 

  • He YF, Li BZ, Li Z, Liu P, Wang Y, Tang Q, Ding J, Jia Y, Chen Z, Li L et al (2011) Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 333:1303–1307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hemerly JP, Bastos AU, Cerutti JM (2010) Identification of several novel non-p.R132 IDH1 variants in thyroid carcinomas. Eur J Endocrinol 163:747–755

    Article  CAS  PubMed  Google Scholar 

  • Hill PWS, Leitch HG, Requena CE, Sun Z, Amouroux R, Roman-Trufero M, Borkowska M, Terragni J, Vaisvila R, Linnett S et al (2018) Epigenetic reprogramming enables the transition from primordial germ cell to gonocyte. Nature 555:392–396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hoffart LM, Barr EW, Guyer RB, Bollinger JM Jr, Krebs C (2006) Direct spectroscopic detection of a C-H-cleaving high-spin Fe(IV) complex in a prolyl-4-hydroxylase. Proc Natl Acad Sci U S A 103:14738–14743

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hoon DS, Spugnardi M, Kuo C, Huang SK, Morton DL, Taback B (2004) Profiling epigenetic inactivation of tumor suppressor genes in tumors and plasma from cutaneous melanoma patients. Oncogene 23:4014–4022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hrit J, Goodrich L, Li C, Wang BA, Nie J, Cui X, Martin EA, Simental E, Fernandez J, Liu MY et al (2018) OGT binds a conserved C-terminal domain of TET1 to regulate TET1 activity and function in development. Elife 7

    Google Scholar 

  • Hu L, Li Z, Cheng J, Rao Q, Gong W, Liu M, Shi YG, Zhu J, Wang P, Xu Y (2013) Crystal structure of TET2-DNA complex: insight into TET-mediated 5mC oxidation. Cell 155:1545–1555

    Article  CAS  PubMed  Google Scholar 

  • Hu X, Zhang L, Mao SQ, Li Z, Chen J, Zhang RR, Wu HP, Gao J, Guo F, Liu W et al (2014) Tet and TDG mediate DNA demethylation essential for mesenchymal-to-epithelial transition in somatic cell reprogramming. Cell Stem Cell 14:512–522

    Article  CAS  PubMed  Google Scholar 

  • Hu L, Lu J, Cheng J, Rao Q, Li Z, Hou H, Lou Z, Zhang L, Li W, Gong W et al (2015) Structural insight into substrate preference for TET-mediated oxidation. Nature 527:118–122

    Article  CAS  PubMed  Google Scholar 

  • Huang W, Lan MD, Qi CB, Zheng SJ, Wei SZ, Yuan BF, Feng YQ (2016) Formation and determination of the oxidation products of 5-methylcytosine in RNA. Chem Sci 7:5495–5502

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Inoue A, Zhang Y (2011) Replication-dependent loss of 5-hydroxymethylcytosine in mouse preimplantation embryos. Science 334:194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iqbal K, Jin SG, Pfeifer GP, Szabo PE (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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ito S, D’Alessio AC, Taranova OV, Hong K, Sowers LC, Zhang Y (2010) Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 466:1129–1133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA, He C, Zhang Y (2011) Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333:1300–1303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iyer LM, Tahiliani M, Rao A, Aravind L (2009) Prediction of novel families of enzymes involved in oxidative and other complex modifications of bases in nucleic acids. Cell Cycle 8:1698–1710

    Article  CAS  PubMed  Google Scholar 

  • Iyer LM, Zhang D, Burroughs AM, Aravind L (2013) Computational identification of novel biochemical systems involved in oxidation, glycosylation and other complex modifications of bases in DNA. Nucleic Acids Res 41:7635–7655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Jeong JJ, Gu X, Nie J, Sundaravel S, Liu H, Kuo WL, Bhagat TD, Pradhan K, Cao J, Nischal S et al (2019) Cytokine-regulated phosphorylation and activation of TET2 by JAK2 in hematopoiesis. Cancer Discov 9:778–795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaas GA, Zhong C, Eason DE, Ross DL, Vachhani RV, Ming GL, King JR, Song H, Sweatt JD (2013) TET1 controls CNS 5-methylcytosine hydroxylation, active DNA demethylation, gene transcription, and memory formation. Neuron 79:1086–1093

    Article  CAS  PubMed  Google Scholar 

  • Kangaspeska S, Stride B, Metivier R, Polycarpou-Schwarz M, Ibberson D, Carmouche RP, Benes V, Gannon F, Reid G (2008) Transient cyclical methylation of promoter DNA. Nature 452:112–115

    Article  CAS  PubMed  Google Scholar 

  • Kavoosi S, Sudhamalla B, Dey D, Shriver K, Arora S, Sappa S, Islam K (2019) Site- and degree-specific C-H oxidation on 5-methylcytosine homologues for probing active DNA demethylation. Chem Sci 10:10550–10555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ko M, Huang Y, Jankowska AM, Pape UJ, Tahiliani M, Bandukwala HS, An J, Lamperti ED, Koh KP, Ganetzky R et al (2010) Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature 468:839–843

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ko M, An J, Bandukwala HS, Chavez L, Aijo T, Pastor WA, Segal MF, Li H, Koh KP, Lahdesmaki H et al (2013) Modulation of TET2 expression and 5-methylcytosine oxidation by the CXXC domain protein IDAX. Nature 497:122–126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Koh KP, Yabuuchi A, Rao S, Huang Y, Cunniff K, Nardone J, Laiho A, Tahiliani M, Sommer CA, Mostoslavsky G et al (2011) Tet1 and Tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells. Cell Stem Cell 8:200–213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Krebs C, Galonic Fujimori D, Walsh CT, Bollinger JM Jr (2007) Non-heme Fe(IV)-oxo intermediates. Acc Chem Res 40:484–492

    Article  CAS  PubMed  Google Scholar 

  • Kriaucionis S, Heintz N (2009) The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science 324:929–930

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kurimoto K, Yabuta Y, Ohinata Y, Shigeta M, Yamanaka K, Saitou M (2008) Complex genome-wide transcription dynamics orchestrated by Blimp1 for the specification of the germ cell lineage in mice. Genes Dev 22:1617–1635

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lan J, Rajan N, Bizet M, Penning A, Singh NK, Guallar D, Calonne E, Li Greci A, Bonvin E, Deplus R et al (2020) Functional role of Tet-mediated RNA hydroxymethylcytosine in mouse ES cells and during differentiation. Nat Commun 11:4956

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Langemeijer SM, Kuiper RP, Berends M, Knops R, Aslanyan MG, Massop M, Stevens-Linders E, van Hoogen P, van Kessel AG, Raymakers RA et al (2009) Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat Genet 41:838–842

    Article  CAS  PubMed  Google Scholar 

  • Laurent L, Wong E, Li G, Huynh T, Tsirigos A, Ong CT, Low HM, Kin Sung KW, Rigoutsos I, Loring J et al (2010) Dynamic changes in the human methylome during differentiation. Genome Res 20:320–331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee J, Inoue K, Ono R, Ogonuki N, Kohda T, Kaneko-Ishino T, Ogura A, Ishino F (2002) Erasing genomic imprinting memory in mouse clone embryos produced from day 11.5 primordial germ cells. Development 129:1807–1817

    Article  CAS  PubMed  Google Scholar 

  • Lee HJ, Hore TA, Reik W (2014) Reprogramming the methylome: erasing memory and creating diversity. Cell Stem Cell 14:710–719

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li X, Wei W, Zhao QY, Widagdo J, Baker-Andresen D, Flavell CR, D’Alessio A, Zhang Y, Bredy TW (2014) Neocortical Tet3-mediated accumulation of 5-hydroxymethylcytosine promotes rapid behavioral adaptation. Proc Natl Acad Sci U S A 111:7120–7125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li H, Hu Z, Jiang H, Pu J, Selli I, Qiu J, Zhang B, Feng J (2020a) TET1 deficiency impairs morphogen-free differentiation of human embryonic stem cells to neuroectoderm. Sci Rep 10:10343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li S, Feng J, Wu F, Cai J, Zhang X, Wang H, Fetahu IS, Iwanicki I, Ma D, Hu T et al (2020b) TET2 promotes anti-tumor immunity by governing G-MDSCs and CD8(+) T-cell numbers. EMBO Rep 21:e49425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li HJ, Wang Y, Li BX, Yang Y, Guan F, Pang XC, Li X (2021a) Roles of ten-eleven translocation family proteins and their O-linked beta-N-acetylglucosaminylated forms in cancer development. Oncol Lett 21:1

    Article  PubMed  Google Scholar 

  • Li W, Zhang T, Sun M, Shi Y, Zhang XJ, Xu GL, Ding J (2021b) Molecular mechanism for vitamin C-derived C(5)-glyceryl-methylcytosine DNA modification catalyzed by algal TET homologue CMD1. Nat Commun 12:744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lian CG, Xu Y, Ceol C, Wu F, Larson A, Dresser K, Xu W, Tan L, Hu Y, Zhan Q et al (2012) Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma. Cell 150:1135–1146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lister R, Pelizzola M, Dowen RH, Hawkins RD, Hon G, Tonti-Filippini J, Nery JR, Lee L, Ye Z, Ngo QM et al (2009) Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462:315–322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lister R, Pelizzola M, Kida YS, Hawkins RD, Nery JR, Hon G, Antosiewicz-Bourget J, O’Malley R, Castanon R, Klugman S et al (2011) Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature 471:68–73

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lister R, Mukamel EA, Nery JR, Urich M, Puddifoot CA, Johnson ND, Lucero J, Huang Y, Dwork AJ, Schultz MD et al (2013) Global epigenomic reconfiguration during mammalian brain development. Science 341:1237905

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu CK, Hsu CA, Abbott MT (1973) Catalysis of three sequential dioxygenase reactions by thymine 7-hydroxylase. Arch Biochem Biophys 159:180–187

    Article  CAS  PubMed  Google Scholar 

  • Liu S, Ren S, Howell P, Fodstad O, Riker AI (2008) Identification of novel epigenetically modified genes in human melanoma via promoter methylation gene profiling. Pigment Cell Melanoma Res 21:545–558

    Article  CAS  PubMed  Google Scholar 

  • Liutkeviciute Z, Lukinavicius G, Masevicius V, Daujotyte D, Klimasauskas S (2009) Cytosine-5-methyltransferases add aldehydes to DNA. Nat Chem Biol 5:400–402

    Article  CAS  PubMed  Google Scholar 

  • Liutkeviciute Z, Kriukiene E, Licyte J, Rudyte M, Urbanaviciute G, Klimasauskas S (2014) Direct decarboxylation of 5-carboxylcytosine by DNA C5-methyltransferases. J Am Chem Soc 136:5884–5887

    Article  CAS  PubMed  Google Scholar 

  • Loenarz C, Schofield CJ (2008) Expanding chemical biology of 2-oxoglutarate oxygenases. Nat Chem Biol 4:152–156

    Article  CAS  PubMed  Google Scholar 

  • Long HK, Blackledge NP, Klose RJ (2013) ZF-CxxC domain-containing proteins, CpG islands and the chromatin connection. Biochem Soc Trans 41:727–740

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu X, Han D, Zhao BS, Song CX, Zhang LS, Dore LC, He C (2015) Base-resolution maps of 5-formylcytosine and 5-carboxylcytosine reveal genome-wide DNA demethylation dynamics. Cell Res 25:386–389

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maiti A, Drohat AC (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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K, Koboldt DC, Fulton RS, Delehaunty KD, McGrath SD et al (2009) Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 361:1058–1066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martinowich K, Hattori D, Wu H, Fouse S, He F, Hu Y, Fan G, Sun YE (2003) DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science 302:890–893

    Article  CAS  PubMed  Google Scholar 

  • Mayer W, Niveleau A, Walter J, Fundele R, Haaf T (2000) Demethylation of the zygotic paternal genome. Nature 403:501–502

    Article  CAS  PubMed  Google Scholar 

  • Maynard JC, Burlingame AL, Medzihradszky KF (2016) Cysteine S-linked N-acetylglucosamine (S-GlcNAcylation), a new post-translational modification in mammals. Mol Cell Proteomics 15:3405–3411

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McDonough MA, Loenarz C, Chowdhury R, Clifton IJ, Schofield CJ (2010) Structural studies on human 2-oxoglutarate dependent oxygenases. Curr Opin Struct Biol 20:659–672

    Article  CAS  PubMed  Google Scholar 

  • Mellen M, Ayata P, Dewell S, Kriaucionis S, Heintz N (2012) MeCP2 binds to 5hmC enriched within active genes and accessible chromatin in the nervous system. Cell 151:1417–1430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Metivier R, Gallais R, Tiffoche C, Le Peron C, Jurkowska RZ, Carmouche RP, Ibberson D, Barath P, Demay F, Reid G et al (2008) Cyclical DNA methylation of a transcriptionally active promoter. Nature 452:45–50

    Article  CAS  PubMed  Google Scholar 

  • Mi Y, Gao X, Dai J, Ma Y, Xu L, Jin W (2015) A novel function of TET2 in CNS: sustaining neuronal survival. Int J Mol Sci 16:21846–21857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Minor EA, Court BL, Young JI, Wang G (2013) Ascorbate induces ten-eleven translocation (Tet) methylcytosine dioxygenase-mediated generation of 5-hydroxymethylcytosine. J Biol Chem 288:13669–13674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moran-Crusio K, Reavie L, Shih A, Abdel-Wahab O, Ndiaye-Lobry D, Lobry C, Figueroa ME, Vasanthakumar A, Patel J, Zhao X et al (2011) Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell 20:11–24

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moyon S, Frawley R, Marechal D, Huang D, Marshall-Phelps KLH, Kegel L, Bostrand SMK, Sadowski B, Jiang YH, Lyons DA et al (2021) TET1-mediated DNA hydroxymethylation regulates adult remyelination in mice. Nat Commun 12:3359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mulholland CB, Traube FR, Ugur E, Parsa E, Eckl EM, Schonung M, Modic M, Bartoschek MD, Stolz P, Ryan J et al (2020) Distinct and stage-specific contributions of TET1 and TET2 to stepwise cytosine oxidation in the transition from naive to primed pluripotency. Sci Rep 10:12066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Muller I, Kahnert A, Pape T, Sheldrick GM, Meyer-Klaucke W, Dierks T, Kertesz M, Uson I (2004) Crystal structure of the alkylsulfatase AtsK: insights into the catalytic mechanism of the Fe(II) alpha-ketoglutarate-dependent dioxygenase superfamily. Biochemistry 43:3075–3088

    Article  PubMed  Google Scholar 

  • Munzel M, Globisch D, Bruckl T, Wagner M, Welzmiller V, Michalakis S, Muller M, Biel M, Carell T (2010) Quantification of the sixth DNA base hydroxymethylcytosine in the brain. Angew Chem Int Ed Engl 49:5375–5377

    Article  PubMed  Google Scholar 

  • Myllyla R, Kuutti-Savolainen ER, Kivirikko KI (1978) The role of ascorbate in the prolyl hydroxylase reaction. Biochem Biophys Res Commun 83:441–448

    Article  CAS  PubMed  Google Scholar 

  • Nabel CS, Jia H, Ye Y, Shen L, Goldschmidt HL, Stivers JT, Zhang Y, Kohli RM (2012) AID/APOBEC deaminases disfavor modified cytosines implicated in DNA demethylation. Nat Chem Biol 8:751–758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nakamura T, Arai Y, Umehara H, Masuhara M, Kimura T, Taniguchi H, Sekimoto T, Ikawa M, Yoneda Y, Okabe M et al (2007) PGC7/Stella protects against DNA demethylation in early embryogenesis. Nat Cell Biol 9:64–71

    Article  CAS  PubMed  Google Scholar 

  • Neidigh JW, Darwanto A, Williams AA, Wall NR, Sowers LC (2009) Cloning and characterization of Rhodotorula glutinis thymine hydroxylase. Chem Res Toxicol 22:885–893

    Article  CAS  PubMed  Google Scholar 

  • Ono R, Taki T, Taketani T, Taniwaki M, Kobayashi H, Hayashi Y (2002) LCX, leukemia-associated protein with a CXXC domain, is fused to MLL in acute myeloid leukemia with trilineage dysplasia having t(10;11)(q22;q23). Cancer Res 62:4075–4080

    CAS  PubMed  Google Scholar 

  • Osipyants AI, Poloznikov AA, Smirnova NA, Hushpulian DM, Khristichenko AY, Chubar TA, Zakhariants AA, Ahuja M, Gaisina IN, Thomas B et al (2018) L-ascorbic acid: A true substrate for HIF prolyl hydroxylase? Biochimie 147:46–54

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Parry A, Rulands S, Reik W (2021) Active turnover of DNA methylation during cell fate decisions. Nat Rev Genet 22:59–66

    Article  CAS  PubMed  Google Scholar 

  • Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL et al (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807–1812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pastor WA, Aravind L, Rao A (2013) TETonic shift: biological roles of TET proteins in DNA demethylation and transcription. Nat Rev Mol Cell Biol 14:341–356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pfaffeneder T, Hackner B, Truss M, Munzel M, Muller M, Deiml CA, Hagemeier C, Carell T (2011) The discovery of 5-formylcytosine in embryonic stem cell DNA. Angew Chem Int Ed Engl 50:7008–7012

    Article  CAS  PubMed  Google Scholar 

  • Pfaffeneder T, Spada F, Wagner M, Brandmayr C, Laube SK, Eisen D, Truss M, Steinbacher J, Hackner B, Kotljarova O et al (2014) Tet oxidizes thymine to 5-hydroxymethyluracil in mouse embryonic stem cell DNA. Nat Chem Biol 10:574–581

    Article  CAS  PubMed  Google Scholar 

  • Price JC, Barr EW, Glass TE, Krebs C, Bollinger JM Jr (2003) Evidence for hydrogen abstraction from C1 of taurine by the high-spin Fe(IV) intermediate detected during oxygen activation by taurine:alpha-ketoglutarate dioxygenase (TauD). J Am Chem Soc 125:13008–13009

    Article  CAS  PubMed  Google Scholar 

  • Quivoron C, Couronne L, Della Valle V, Lopez CK, Plo I, Wagner-Ballon O, Do Cruzeiro M, Delhommeau F, Arnulf B, Stern MH et al (2011) TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis. Cancer Cell 20:25–38

    Article  CAS  PubMed  Google Scholar 

  • Rampal R, Alkalin A, Madzo J, Vasanthakumar A, Pronier E, Patel J, Li Y, Ahn J, Abdel-Wahab O, Shih A et al (2014) DNA hydroxymethylation profiling reveals that WT1 mutations result in loss of TET2 function in acute myeloid leukemia. Cell Rep 9:1841–1855

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rangam G, Schmitz KM, Cobb AJ, Petersen-Mahrt SK (2012) AID enzymatic activity is inversely proportional to the size of cytosine C5 orbital cloud. PLoS One 7:e43279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rao LJ, Yi BC, Li QM, Xu Q (2016) TET1 knockdown inhibits the odontogenic differentiation potential of human dental pulp cells. Int J Oral Sci 8:110–116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rasmussen KD, Helin K (2016) Role of TET enzymes in DNA methylation, development, and cancer. Genes Dev 30:733–750

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rodic N, Zampella J, Sharma R, Burns KH, Taube JM (2015) Diagnostic utility of 5-hydroxymethylcytosine immunohistochemistry in melanocytic proliferations. J Cutan Pathol 42:807–814

    Article  PubMed  PubMed Central  Google Scholar 

  • Rudenko A, Dawlaty MM, Seo J, Cheng AW, Meng J, Le T, Faull KF, Jaenisch R, Tsai LH (2013) Tet1 is critical for neuronal activity-regulated gene expression and memory extinction. Neuron 79:1109–1122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rulands S, Lee HJ, Clark SJ, Angermueller C, Smallwood SA, Krueger F, Mohammed H, Dean W, Nichols J, Rugg-Gunn P et al (2018) Genome-scale oscillations in DNA methylation during exit from pluripotency. Cell Syst 7:63–76 e12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ruzov A, Tsenkina Y, Serio A, Dudnakova T, Fletcher J, Bai Y, Chebotareva T, Pells S, Hannoun Z, Sullivan G et al (2011) Lineage-specific distribution of high levels of genomic 5-hydroxymethylcytosine in mammalian development. Cell Res 21:1332–1342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ryle MJ, Padmakumar R, Hausinger RP (1999) Stopped-flow kinetic analysis of Escherichia coli taurine/alpha-ketoglutarate dioxygenase: interactions with alpha-ketoglutarate, taurine, and oxygen. Biochemistry 38:15278–15286

    Article  CAS  PubMed  Google Scholar 

  • Saitou M, Kagiwada S, Kurimoto K (2012) Epigenetic reprogramming in mouse pre-implantation development and primordial germ cells. Development 139:15–31

    Article  CAS  PubMed  Google Scholar 

  • Santiago M, Antunes C, Guedes M, Iacovino M, Kyba M, Reik W, Sousa N, Pinto L, Branco MR, Marques CJ (2020) Tet3 regulates cellular identity and DNA methylation in neural progenitor cells. Cell Mol Life Sci 77:2871–2883

    Article  CAS  PubMed  Google Scholar 

  • Schiesser S, Hackner B, Pfaffeneder T, Muller M, Hagemeier C, Truss M, Carell T (2012) Mechanism and stem-cell activity of 5-carboxycytosine decarboxylation determined by isotope tracing. Angew Chem Int Ed Engl 51:6516–6520

    Article  CAS  PubMed  Google Scholar 

  • Schutsky EK, DeNizio JE, Hu P, Liu MY, Nabel CS, Fabyanic EB, Hwang Y, Bushman FD, Wu H, Kohli RM (2018) Nondestructive, base-resolution sequencing of 5-hydroxymethylcytosine using a DNA deaminase. Nat Biotechnol. https://doi.org/10.1038/nbt.4204

  • Seisenberger S, Andrews S, Krueger F, Arand J, Walter J, Santos F, Popp C, Thienpont B, Dean W, Reik W (2012) The dynamics of genome-wide DNA methylation reprogramming in mouse primordial germ cells. Mol Cell 48:849–862

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shen L, Kondo Y, Guo Y, Zhang J, Zhang L, Ahmed S, Shu J, Chen X, Waterland RA, Issa JP (2007) Genome-wide profiling of DNA methylation reveals a class of normally methylated CpG island promoters. PLoS Genet 3:2023–2036

    Article  CAS  PubMed  Google Scholar 

  • Shen L, Wu H, Diep D, Yamaguchi S, D’Alessio AC, Fung HL, Zhang K, Zhang Y (2013) Genome-wide analysis reveals TET- and TDG-dependent 5-methylcytosine oxidation dynamics. Cell 153:692–706

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shen L, Inoue A, He J, Liu Y, Lu F, Zhang Y (2014a) Tet3 and DNA replication mediate demethylation of both the maternal and paternal genomes in mouse zygotes. Cell Stem Cell 15:459–471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shen L, Song CX, He C, Zhang Y (2014b) Mechanism and function of oxidative reversal of DNA and RNA methylation. Annu Rev Biochem 83:585–614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shen H, Ontiveros RJ, Owens MC, Liu MY, Ghanty U, Kohli RM, Liu KF (2021a) TET-mediated 5-methylcytosine oxidation in tRNA promotes translation. J Biol Chem 296:100087

    Article  CAS  PubMed  Google Scholar 

  • Shen Y, Liu L, Wang M, Xu B, Lyu R, Shi YG, Tan L (2021b) TET2 Inhibits PD-L1 gene expression in breast cancer cells through histone deacetylation. Cancers (Basel):13

    Google Scholar 

  • Shibata T, Kokubu A, Miyamoto M, Sasajima Y, Yamazaki N (2011) Mutant IDH1 confers an in vivo growth in a melanoma cell line with BRAF mutation. Am J Pathol 178:1395–1402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smiley JA, Kundracik M, Landfried DA, Barnes VR Sr, Axhemi AA (2005) Genes of the thymidine salvage pathway: thymine-7-hydroxylase from a Rhodotorula glutinis cDNA library and iso-orotate decarboxylase from Neurospora crassa. Biochim Biophys Acta 1723:256–264

    Article  CAS  PubMed  Google Scholar 

  • Smith ZD, Meissner A (2013) DNA methylation: roles in mammalian development. Nat Rev Genet 14:204–220

    Article  CAS  PubMed  Google Scholar 

  • Song CX, Szulwach KE, Fu Y, Dai Q, Yi C, Li X, Li Y, Chen CH, Zhang W, Jian X et al (2011) Selective chemical labeling reveals the genome-wide distribution of 5-hydroxymethylcytosine. Nat Biotechnol 29:68–72

    Article  CAS  PubMed  Google Scholar 

  • Song CX, Szulwach KE, Dai Q, Fu Y, Mao SQ, Lin L, Street C, Li Y, Poidevin M, Wu H et al (2013) Genome-wide profiling of 5-formylcytosine reveals its roles in epigenetic priming. Cell 153:678–691

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Song Y, van den Berg PR, Markoulaki S, Soldner F, Dall’Agnese A, Henninger JE, Drotar J, Rosenau N, Cohen MA, Young RA et al (2019) Dynamic enhancer DNA methylation as basis for transcriptional and cellular heterogeneity of ESCs. Mol Cell 75:905–920 e906

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Spada F, Schiffers S, Kirchner A, Zhang Y, Arista G, Kosmatchev O, Korytiakova E, Rahimoff R, Ebert C, Carell T (2020) Active turnover of genomic methylcytosine in pluripotent cells. Nat Chem Biol 16:1411–1419

    Article  CAS  PubMed  Google Scholar 

  • Szwagierczak A, Bultmann S, Schmidt CS, Spada F, Leonhardt H (2010) Sensitive enzymatic quantification of 5-hydroxymethylcytosine in genomic DNA. Nucleic Acids Res 38:e181

    Article  PubMed  PubMed Central  Google Scholar 

  • Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, Agarwal S, Iyer LM, Liu DR, Aravind L et al (2009) Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324:930–935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tamanaha E, Guan S, Marks K, Saleh L (2016) Distributive processing by the iron(II)/alpha-ketoglutarate-dependent catalytic domains of the TET enzymes is consistent with epigenetic roles for oxidized 5-methylcytosine bases. J Am Chem Soc 138:9345–9348

    Article  CAS  PubMed  Google Scholar 

  • Tan L, Shi YG (2012) Tet family proteins and 5-hydroxymethylcytosine in development and disease. Development 139:1895–1902

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tefferi A, Levine RL, Lim KH, Abdel-Wahab O, Lasho TL, Patel J, Finke CM, Mullally A, Li CY, Pardanani A et al (2009) Frequent TET2 mutations in systemic mastocytosis: clinical, KITD816V and FIP1L1-PDGFRA correlates. Leukemia 23:900–904

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tsai CL, Tainer JA (2013) Probing DNA by 2-OG-dependent dioxygenase. Cell 155:1448–1450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Valegard K, Terwisscha van Scheltinga AC, Dubus A, Ranghino G, Oster LM, Hajdu J, Andersson I (2004) The structural basis of cephalosporin formation in a mononuclear ferrous enzyme. Nat Struct Mol Biol 11:95–101

    Article  CAS  PubMed  Google Scholar 

  • Valinluck V, Sowers LC (2007) Endogenous cytosine damage products alter the site selectivity of human DNA maintenance methyltransferase DNMT1. Cancer Res 67:946–950

    Article  CAS  PubMed  Google Scholar 

  • Valinluck V, Tsai HH, Rogstad DK, Burdzy A, Bird A, Sowers LC (2004) Oxidative damage to methyl-CpG sequences inhibits the binding of the methyl-CpG binding domain (MBD) of methyl-CpG binding protein 2 (MeCP2). Nucleic Acids Res 32:4100–4108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • van der Wijst MG, Venkiteswaran M, Chen H, Xu GL, Plosch T, Rots MG (2015) Local chromatin microenvironment determines DNMT activity: from DNA methyltransferase to DNA demethylase or DNA dehydroxymethylase. Epigenetics 10:671–676

    Article  PubMed  PubMed Central  Google Scholar 

  • Vella P, Scelfo A, Jammula S, Chiacchiera F, Williams K, Cuomo A, Roberto A, Christensen J, Bonaldi T, Helin K et al (2013) Tet proteins connect the O-linked N-acetylglucosamine transferase Ogt to chromatin in embryonic stem cells. Mol Cell 49:645–656

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Zhang Y (2014) Regulation of TET protein stability by calpains. Cell Rep 6:278–284

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang T, Chen K, Zeng X, Yang J, Wu Y, Shi X, Qin B, Zeng L, Esteban MA, Pan G et al (2011) The histone demethylases Jhdm1a/1b enhance somatic cell reprogramming in a vitamin-C-dependent manner. Cell Stem Cell 9:575–587

    Article  CAS  PubMed  Google Scholar 

  • Wang L, Zhang J, Duan J, Gao X, Zhu W, Lu X, Yang L, Zhang J, Li G, Ci W et al (2014) Programming and inheritance of parental DNA methylomes in mammals. Cell 157:979–991

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang L, Zhou Y, Xu L, Xiao R, Lu X, Chen L, Chong J, Li H, He C, Fu XD et al (2015a) Molecular basis for 5-carboxycytosine recognition by RNA polymerase II elongation complex. Nature 523:621–625

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Y, Xiao M, Chen X, Chen L, Xu Y, Lv L, Wang P, Yang H, Ma S, Lin H et al (2015b) WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell proliferation. Mol Cell 57:662–673

    Article  PubMed  PubMed Central  Google Scholar 

  • Weng YL, An R, Cassin J, Joseph J, Mi R, Wang C, Zhong C, Jin SG, Pfeifer GP, Bellacosa A et al (2017) An intrinsic epigenetic barrier for functional axon regeneration. Neuron 94:337–346 e336

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Williams K, Christensen J, Helin K (2011a) DNA methylation: TET proteins-guardians of CpG islands? EMBO Rep 13:28–35

    Article  PubMed  PubMed Central  Google Scholar 

  • Williams K, Christensen J, Pedersen MT, Johansen JV, Cloos PA, Rappsilber J, Helin K (2011b) TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity. Nature 473:343–348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wossidlo M, Nakamura T, Lepikhov K, Marques CJ, Zakhartchenko V, Boiani M, Arand J, Nakano T, Reik W, Walter J (2011) 5-Hydroxymethylcytosine in the mammalian zygote is linked with epigenetic reprogramming. Nat Commun 2:241

    Article  PubMed  Google Scholar 

  • Wu SC, Zhang Y (2010) Active DNA demethylation: many roads lead to Rome. Nat Rev Mol Cell Biol 11:607–620

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu H, Zhang Y (2011) Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. Genes Dev 25:2436–2452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu H, Zhang Y (2014) Reversing DNA methylation: mechanisms, genomics, and biological functions. Cell 156:45–68

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu X, Zhang Y (2017) TET-mediated active DNA demethylation: mechanism, function and beyond. Nat Rev Genet 18:517–534

    Article  CAS  PubMed  Google Scholar 

  • Wu H, D’Alessio AC, Ito S, Xia K, Wang Z, Cui K, Zhao K, Sun YE, Zhang Y (2011) Dual functions of Tet1 in transcriptional regulation in mouse embryonic stem cells. Nature 473:389–393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xia B, Han D, Lu X, Sun Z, Zhou A, Yin Q, Zeng H, Liu M, Jiang X, Xie W et al (2015) Bisulfite-free, base-resolution analysis of 5-formylcytosine at the genome scale. Nat Methods 12:1047–1050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xiao M, Yang H, Xu W, Ma S, Lin H, Zhu H, Liu L, Liu Y, Yang C, Xu Y et al (2012) Inhibition of alpha-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev 26:1326–1338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xie W, Barr CL, Kim A, Yue F, Lee AY, Eubanks J, Dempster EL, Ren B (2012) Base-resolution analyses of sequence and parent-of-origin dependent DNA methylation in the mouse genome. Cell 148:816–831

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xing X, Sato S, Wong NK, Hidaka K, Sugiyama H, Endo M (2020) Direct observation and analysis of TET-mediated oxidation processes in a DNA origami nanochip. Nucleic Acids Res 48:4041–4051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu GL, Walsh CP (2014) Enzymatic DNA oxidation: mechanisms and biological significance. BMB Rep 47:609–618

    Article  PubMed  PubMed Central  Google Scholar 

  • Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, Ito S, Yang C, Wang P, Xiao MT et al (2011a) Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell 19:17–30

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu Y, Wu F, Tan L, Kong L, Xiong L, Deng J, Barbera AJ, Zheng L, Zhang H, Huang S et al (2011b) Genome-wide regulation of 5hmC, 5mC, and gene expression by Tet1 hydroxylase in mouse embryonic stem cells. Mol Cell 42:451–464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu Y, Xu C, Kato A, Tempel W, Abreu JG, Bian C, Hu Y, Hu D, Zhao B, Cerovina T et al (2012) Tet3 CXXC domain and dioxygenase activity cooperatively regulate key genes for Xenopus eye and neural development. Cell 151:1200–1213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu S, Li W, Zhu J, Wang R, Li Z, Xu GL, Ding J (2013) Crystal structures of isoorotate decarboxylases reveal a novel catalytic mechanism of 5-carboxyl-uracil decarboxylation and shed light on the search for DNA decarboxylase. Cell Res 23:1296–1309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu L, Chen Y-C, Chong J, Fin A, McCoy LS, Xu J, Zhang C, Wang D (2014) Pyrene-based quantitative detection of the 5-formylcytosine loci symmetry in the CpG Duplex content during TET-dependent demethylation. Angewandte Chemie 126:11405–11409

    Article  Google Scholar 

  • Xu Q, Wang K, Wang L, Zhu Y, Zhou G, Xie D, Yang Q (2016) IDH1/2 mutants inhibit TET-promoted oxidation of RNA 5mC to 5hmC. PLoS One 11:e0161261

    Article  PubMed  PubMed Central  Google Scholar 

  • Yamaguchi S, Hong K, Liu R, Shen L, Inoue A, Diep D, Zhang K, Zhang Y (2012) Tet1 controls meiosis by regulating meiotic gene expression. Nature 492:443–447

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamaguchi S, Shen L, Liu Y, Sendler D, Zhang Y (2013) Role of Tet1 in erasure of genomic imprinting. Nature 504:460–464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamazaki Y, Mann MR, Lee SS, Marh J, McCarrey JR, Yanagimachi R, Bartolomei MS (2003) Reprogramming of primordial germ cells begins before migration into the genital ridge, making these cells inadequate donors for reproductive cloning. Proc Natl Acad Sci U S A 100:12207–12212

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang CG, Yi C, Duguid EM, Sullivan CT, Jian X, Rice PA, He C (2008) Crystal structures of DNA/RNA repair enzymes AlkB and ABH2 bound to dsDNA. Nature 452:961–965

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang CG, Garcia K, He C (2009) Damage detection and base flipping in direct DNA alkylation repair. Chembiochem 10:417–423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang H, Liu Y, Bai F, Zhang JY, Ma SH, Liu J, Xu ZD, Zhu HG, Ling ZQ, Ye D et al (2013) Tumor development is associated with decrease of TET gene expression and 5-methylcytosine hydroxylation. Oncogene 32:663–669

    Article  CAS  PubMed  Google Scholar 

  • Ye D, Ma S, Xiong Y, Guan KL (2013) R-2-hydroxyglutarate as the key effector of IDH mutations promoting oncogenesis. Cancer Cell 23:274–276

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yildirim O, Li R, Hung JH, Chen PB, Dong X, Ee LS, Weng Z, Rando OJ, Fazzio TG (2011) Mbd3/NURD complex regulates expression of 5-hydroxymethylcytosine marked genes in embryonic stem cells. Cell 147:1498–1510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yin R, Mao SQ, Zhao B, Chong Z, Yang Y, Zhao C, Zhang D, Huang H, Gao J, Li Z et al (2013) Ascorbic acid enhances Tet-mediated 5-methylcytosine oxidation and promotes DNA demethylation in mammals. J Am Chem Soc 135:10396–10403

    Article  CAS  PubMed  Google Scholar 

  • Young JI, Zuchner S, Wang G (2015) Regulation of the epigenome by vitamin C. Annu Rev Nutr 35:545–564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu Z, Genest PA, ter Riet B, Sweeney K, DiPaolo C, Kieft R, Christodoulou E, Perrakis A, Simmons JM, Hausinger RP et al (2007) The protein that binds to DNA base J in trypanosomatids has features of a thymidine hydroxylase. Nucleic Acids Res 35:2107–2115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu M, Hon GC, Szulwach KE, Song CX, Zhang L, Kim A, Li X, Dai Q, Shen Y, Park B et al (2012) Base-resolution analysis of 5-hydroxymethylcytosine in the mammalian genome. Cell 149:1368–1380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu H, Su Y, Shin J, Zhong C, Guo JU, Weng YL, Gao F, Geschwind DH, Coppola G, Ming GL et al (2015) Tet3 regulates synaptic transmission and homeostatic plasticity via DNA oxidation and repair. Nat Neurosci 18:836–843

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yue X, Trifari S, Aijo T, Tsagaratou A, Pastor WA, Zepeda-Martinez JA, Lio CW, Li X, Huang Y, Vijayanand P et al (2016) Control of Foxp3 stability through modulation of TET activity. J Exp Med 213:377–397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yue X, Samaniego-Castruita D, Gonzalez-Avalos E, Li X, Barwick BG, Rao A (2021) Whole-genome analysis of TET dioxygenase function in regulatory T cells. EMBO Rep 22:e52716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang L, Lu X, Lu J, Liang H, Dai Q, Xu GL, Luo C, Jiang H, He C (2012) Thymine DNA glycosylase specifically recognizes 5-carboxylcytosine-modified DNA. Nat Chem Biol 8:328–330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang G, Huang H, Liu D, Cheng Y, Liu X, Zhang W, Yin R, Zhang D, Zhang P, Liu J et al (2015a) N6-methyladenine DNA modification in Drosophila. Cell 161:893–906

    Article  CAS  PubMed  Google Scholar 

  • Zhang Q, Zhao K, Shen Q, Han Y, Gu Y, Li X, Zhao D, Liu Y, Wang C, Zhang X et al (2015b) Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6. Nature 525:389–393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang HY, Xiong J, Qi BL, Feng YQ, Yuan BF (2016a) The existence of 5-hydroxymethylcytosine and 5-formylcytosine in both DNA and RNA in mammals. Chem Commun (Camb) 52:737–740

    Article  CAS  Google Scholar 

  • Zhang X, Su J, Jeong M, Ko M, Huang Y, Park HJ, Guzman A, Lei Y, Huang YH, Rao A et al (2016b) DNMT3A and TET2 compete and cooperate to repress lineage-specific transcription factors in hematopoietic stem cells. Nat Genet 48:1014–1023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou T, Xiong J, Wang M, Yang N, Wong J, Zhu B, Xu RM (2014) Structural basis for hydroxymethylcytosine recognition by the SRA domain of UHRF2. Mol Cell 54:879–886

    Article  CAS  PubMed  Google Scholar 

  • Ziller MJ, Muller F, Liao J, Zhang Y, Gu H, Bock C, Boyle P, Epstein CB, Bernstein BE, Lengauer T et al (2011) Genomic distribution and inter-sample variation of non-CpG methylation across human cell types. PLoS Genet 7:e1002389

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (31425008 and 91419301). We apologize that we could not cite many important papers due to space limitation.

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Authors and Affiliations

  1. Fudan University Shanghai Cancer Center, Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China

    Xiaotong Yin, Lulu Hu & Yanhui Xu

  2. Key Laboratory of Molecular Medicine, Ministry of Education, Department of Systems Biology for Medicine, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China

    Lulu Hu & Yanhui Xu

  3. State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China

    Yanhui Xu

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  1. Xiaotong Yin
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  2. Lulu Hu
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  3. Yanhui Xu
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Correspondence to Lulu Hu or Yanhui Xu .

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Editors and Affiliations

  1. Department of Biochemistry, Institute of Biochemistry and Technical Biochemistry, University of Stuttgart, Stuttgart, Germany

    Albert Jeltsch

  2. School of Biosciences, Division of Biomedicine, Cardiff University, Cardiff, UK

    Renata Z. Jurkowska

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Yin, X., Hu, L., Xu, Y. (2022). Structure and Function of TET Enzymes. In: Jeltsch, A., Jurkowska, R.Z. (eds) DNA Methyltransferases - Role and Function. Advances in Experimental Medicine and Biology, vol 1389. Springer, Cham. https://doi.org/10.1007/978-3-031-11454-0_10

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