The function and regulation of TET2 in innate immunity and inflammation

Abstract

TET2, a member of ten-eleven translocation (TET) family as α-ketoglutarate- and Fe²⁺-dependent dioxygenase catalyzing the iterative oxidation of 5-methylcytosine (5mC), has been widely recognized to be an important regulator for normal hematopoiesis especially myelopoiesis. Mutation and dysregulation of TET2 contribute to the development of multiple hematological malignancies. Recent studies reveal that TET2 also plays an important role in innate immune homeostasis by promoting DNA demethylation or independent of its enzymatic activity. Here, we focus on the functions of TET2 in the initiation and resolution of inflammation through epigenetic regulation and signaling network. In addition, we highlight regulation of TET2 at various molecular levels as well as the correlated inflammatory diseases, which will provide the insight to intervene in the pathological process caused by TET2 dysregulation.

Key words： TET2; innate immune response; DNA demethylation; inflammatory resolution; inflammatory diseases

References

1 Alvarez-Errico D, Vento-Tormo R, Sieweke M, Ballestar E (2015) Epigenetic control of myeloid cell differentiation, identity and function. Nat Rev Immunol 15:7–17

2 Bauer C, Gobel K, Nagaraj N, Colantuoni C, Wang M, Muller U, Kremmer E, Rottach A, Leonhardt H (2015) Phosphorylation of TET proteins is regulated via O-GlcNAcylation by the O-linked N-acetylglucosamine transferase (OGT). J Biol Chem 290:4801–4812

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

4 Buckley CD, Gilroy DW, Serhan CN, Stockinger B, Tak PP (2013) The resolution of inflammation. Nat Rev Immunol 13:59–66

5 Cao X (2016) Self-regulation and cross-regulation of pattern-recognition receptor signalling in health and disease. Nat Rev Immunol 16:35–50

6 Chen LL, Lin HP, Zhou WJ, He CX, Zhang ZY, Cheng ZL, Song JB, Liu P, Chen XY, Xia YK (2018) SNIP1 recruits TET2 to regulate c-MYC target genes and cellular DNA damage response. Cell Rep 25(1485–1500):e1484

7 Cull AH, Mahendru D, Snetsinger B, Good D, Tyryshkin K, Chesney A, Ghorab Z, Reis M, Buckstein R, Wells RA (2018) Overexpression of Arginase 1 is linked to DNMT3A and TET2 mutations in lower-grade myelodysplastic syndromes and chronic myelomonocytic leukemia. Leuk Res 65:5–13

8 Cull AH, Snetsinger B, Buckstein R, Wells RA, Rauh MJ (2017) TET2 restrains inflammatory gene expression in macrophages. Exp Hematol 55(56–70):e13

9 de Andres MC, Perez-Pampin E, Calaza M, Santaclara FJ, Ortea I, Gomez-Reino JJ, Gonzalez A (2015) Assessment of global DNA methylation in peripheral blood cell subpopulations of early rheumatoid arthritis before and after methotrexate. Arthritis Res Ther 17:233

10 Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Masse A, Kosmider O, Le Couedic JP, Robert F, Alberdi A (2009) Mutation in TET2 in myeloid cancers. N Engl J Med 360:2289–2301

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

12 Fuster JJ, MacLauchlan S, Zuriaga MA, Polackal MN, Ostriker AC, Chakraborty R, Wu CL, Sano S, Muralidharan S, Rius C (2017) Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science 355:842–847

13 Gong D, Zhang Q, Chen LY, Yu XH, Wang G, Zou J, Zheng XL, Zhang DW, Yin WD, Tang CK (2019) Coiled-coil domaincontaining 80 accelerates atherosclerosis development through decreasing lipoprotein lipase expression via ERK1/2 phosphorylation and TET2 expression. Eur J Pharmacol 843:177–189

14 Guallar D, Bi X, Pardavila JA, Huang X, Saenz C, Shi X, Zhou H, Faiola F, Ding J, Haruehanroengra P (2018) RNA-dependent chromatin targeting of TET2 for endogenous retrovirus control in pluripotent stem cells. Nat Genet 50:443–451

15 He C, Sidoli S, Warneford-Thomson R, Tatomer DC, Wilusz JE, Garcia BA, Bonasio R (2016) High-resolution mapping of RNAbinding regions in the nuclear proteome of embryonic stem cells. Mol Cell 64:416–430

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

17 Hore TA, von Meyenn F, Ravichandran M, Bachman M, Ficz G, Oxley D, Santos F, Balasubramanian S, Jurkowski TP, Reik W (2016) Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naive pluripotency by complementary mechanisms. Proc Natl Acad Sci USA 113:12202–12207

18 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

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

20 Jiang S, Yan W, Wang SE, Baltimore D (2019) Dual mechanisms of posttranscriptional regulation of TET2 by Let-7 microRNA in macrophages. Proc Natl Acad Sci USA 116(25):12416–12421

21 Jiao J, Jin Y, Zheng M, Zhang H, Yuan M, Lv Z, Odhiambo W, Yu X, Zhang P, Li C(2019) AID and TET2 co-operation modulates FANCA expression by active demethylation in diffuse large B cell lymphoma. Clin Exp Immunol 195:190–201

22 Jones PA (2012) Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet 13:484–492

23 Kallin EM, Rodriguez-Ubreva J, Christensen J, Cimmino L, Aifantis I, Helin K, Ballestar E, Graf T (2012) TET2 facilitates the derepression of myeloid target genes during CEBPalpha-induced transdifferentiation of pre-B cells. Mol Cell 48:266–276

24 Killian JK, Kim SY, Miettinen M, Smith C, Merino M, Tsokos M, Quezado M, Smith WI Jr, Jahromi MS, Xekouki P (2013) Succinate dehydrogenase mutation underlies global epigenomic divergence in gastrointestinal stromal tumor. Cancer Discov 3:648–657

25 Klutstein M, Nejman D, Greenfield R, Cedar H (2016) DNA methylation in cancer and aging. Cancer Res 76:3446–3450

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

27 Kundu A, Shelar S, Ghosh A, Ballestas M, Kirkman R, Nam HY, Brinkley G, Karki S, Mobley JA, Bae S (2020) 14-3-3proteins protect AMPK-phosphorylated ten-eleven translocation-2 (TET2) from PP2A-mediated dephosphorylation. J Biol Chem. 295(6):1754–1766

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

29 Li B, Zang G, Zhong W, Chen R, Zhang Y, Yang P, Yan J (2020) Activation of CD137 signaling promotes neointimal formation by attenuating TET2 and transferrring from endothelial cell-derived exosomes to vascular smooth muscle cells. Biomed Pharmacother 121:109593

30 Lio CJ, Rao A (2019) TET enzymes and 5hmC in adaptive and innate immune systems. Front Immunol 10:210

31 Liu R, Jin Y, Tang WH, Qin L, Zhang X, Tellides G, Hwa J, Yu J, Martin KA (2013) Ten-eleven translocation-2 (TET2) is a master regulator of smooth muscle cell plasticity. Circulation 128:2047–2057

32 Loenarz C, Schofield CJ (2011) Physiological and biochemical aspects of hydroxylations and demethylations catalyzed by human 2-oxoglutarate oxygenases. Trends Biochem Sci 36:7–18

33 Lv L, Wang Q, Xu Y, Tsao LC, Nakagawa T, Guo H, Su L, Xiong Y (2018) Vpr targets TET2 for degradation by CRL4(VprBP) E3 ligase to sustain IL-6 expression and enhance HIV-1 replication. Mol Cell 70(961–970):e965

34 Ma S, Wan X, Deng Z, Shi L, Hao C, Zhou Z, Zhou C, Fang Y, Liu J, Yang J (2017) Epigenetic regulator CXXC5 recruits DNA demethylase TET2 to regulate TLR7/9-elicited IFN response in pDCs. J Exp Med 214:1471–1491

35 MacFarlane AJ, Strom A, Scott FW (2009) Epigenetics: deciphering how environmental factors may modify autoimmune type 1 diabetes. Mamm Genome 20:624–632

36 Meda F, Folci M, Baccarelli A, Selmi C (2011) The epigenetics of autoimmunity. Cell Mol Immunol 8:226–236

37 Medzhitov R (2008) Origin and physiological roles of inflammation. Nature 454:428–435

38 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

39 Montagner S, Leoni C, Emming S, Della Chiara G, Balestrieri C, Barozzi I, Piccolo V, Togher S, Ko M, Rao A (2016) TET2 regulates mast cell differentiation and proliferation through catalytic and non-catalytic activities. Cell Rep 15:1566–1579

40 Nakagawa T, Lv L, Nakagawa M, Yu Y, Yu C, D’Alessio AC, Nakayama K, Fan HY, Chen X, Xiong Y (2015) CRL4(VprBP) E3 ligase promotes monoubiquitylation and chromatin binding of TET dioxygenases. Mol Cell 57:247–260

41 O’Neill LA, Golenbock D, Bowie AG (2013) The history of Toll-like receptors- redefining innate immunity. Nat Rev Immunol 13:453–460

42 Pan W, Zhu S, Qu K, Meeth K, Cheng J, He K, Ma H, Liao Y, Wen X, Roden C (2017) The DNA methylcytosine dioxygenase TET2 sustains immunosuppressive function of tumor-infiltrating myeloid cells to promote melanoma progression. Immunity 47 (284–297):e285

43 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

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

45 Ren S, Xu Y (2019) AC016405.3, a novel long noncoding RNA, acts as a tumor suppressor through modulation of TET2 by micro-RNA-19a-5p sponging in glioblastoma. Cancer Sci 110:1621–1632

46 Scherm MG, Serr I, Zahm AM, Schug J, Bellusci S, Manfredini R, Salb VK, Gerlach K, Weigmann B, Ziegler AG (2019) miRNA142-3p targets TET2 and impairs Treg differentiation and stability in models of type 1 diabetes. Nat Commun 10:5697

47 Shen Q, Zhang Q, Shi Y, Shi Q, Jiang Y, Gu Y, Li Z, Li X, Zhao K, Wang C (2018) TET2 promotes pathogen infection-induced myelopoiesis through mRNA oxidation. Nature 554:123–127

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

49 Stefan-Lifshitz M, Karakose E, Cui L, Ettela A, Yi Z, Zhang W, Tomer Y (2019) Epigenetic modulation of beta cells by interferon-alpha via PNPT1/mir-26a/TET2 triggers autoimmune diabetes. JCI Insight 4(5):e126663

50 Sun F, Abreu-Rodriguez I, Ye S, Gay S, Distler O, Neidhart M, Karouzakis E (2019) TET1 is an important transcriptional activator of TNFalpha expression in macrophages. PLoS One 14:e0218551

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

52 Tanaka S, Ise W, Inoue T, Ito A, Ono C, Shima Y, Sakakibara S, Nakayama M, Fujii K, Miura I (2020) TET2 and Tet3 in B cells are required to repress CD86 and prevent autoimmunity. Nat Immunol. 31:950–961

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

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

55 Wu D, Hu D, Chen H, Shi G, Fetahu IS, Wu F, Rabidou K, Fang R, Tan L, Xu S (2018) Glucose-regulated phosphorylation of TET2 by AMPK reveals a pathway linking diabetes to cancer. Nature 559:637–641

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

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

58 Xue S, Liu C, Sun X, Li W, Zhang C, Zhou X, Lu Y, Xiao J, Li C, Xu X (2016) TET3 Inhibits Type I IFN Production Independent of DNA Demethylation. Cell Rep 16:1096–1105

59 Yang H, Lin H, Xu H, Zhang L, Cheng L, Wen B, Shou J, Guan K, Xiong Y, Ye D (2014) TET-catalyzed 5-methylcytosine hydroxylation is dynamically regulated by metabolites. Cell Res 24:1017–1020

60 Yang L, Zhang Q, Wu Q, Wei Y, Yu J, Mu J, Zhang J, Zeng W, Feng B (2018) Effect of TET2 on the pathogenesis of diabetic nephropathy through activation of transforming growth factor beta1 expression via DNA demethylation. Life Sci 207:127–137

61 Yang R, Qu C, Zhou Y, Konkel JE, Shi S, Liu Y, Chen C, Liu S, Liu D, Chen Y (2015) Hydrogen sulfide promotes Tet1- and TET2-mediated Foxp3 demethylation to drive regulatory T cell differentiation and maintain immune homeostasis. Immunity 43:251–263

62 Yin R, Mo J, Dai J, Wang H (2017) Nickel(II) Inhibits Tet-mediated 5-methylcytosine oxidation by high affinity displacement of the cofactor iron(II). ACS Chem Biol 12:1494–1498

63 Yue X, Lio CJ, Samaniego-Castruita D, Li X, Rao A (2019) Loss of TET2 and TET3 in regulatory T cells unleashes effector function. Nat Commun 10:2011

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

65 Zhang Q, Zhao K, Shen Q, Han Y, Gu Y, Li X, Zhao D, Liu Y, Wang C, Zhang X (2015) TET2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6. Nature 525:389–393

66 Zhang P, Chu T, Dedousis N, Mantell BS, Sipula I, Li L, Bunce KD, Shaw PA, Katz LS, Zhu J (2017a) DNA methylation alters transcriptional rates of differentially expressed genes and contributes to pathophysiology in mice fed a high fat diet. Mol Metab 6:327–339

67 Zhang YW, Wang Z, Xie W, Cai Y, Xia L, Easwaran H, Luo J, Yen RC, Li Y, Baylin SB (2017b) Acetylation enhances TET2 function in protecting against abnormal DNA methylation during oxidative stress. Mol Cell 65:323–335

68 Zhang TJ, Zhou JD, Yang DQ, Wang YX, Wen XM, Guo H, Yang L, Lian XY, Lin J, Qian J(2018) TET2 expression is a potential prognostic and predictive biomarker in cytogenetically normal acute myeloid leukemia. J Cell Physiol 233:5838–5846

69 Zhang Q, Cao X (2019) Epigenetic regulation of the innate immune response to infection. Nat Rev Immunol. 19:417–432

70 Zhang J, Tan P, Guo L, Gong J, Ma J, Li J, Lee M, Fang S, Jing J, Johnson G (2019a) p53-dependent autophagic degradation of TET2 modulates cancer therapeutic resistance. Oncogene 38:1905–1919

71 Zhang T, Guan X, Choi UL, Dong Q, Lam MMT, Zeng J, Xiong J, Wang X, Poon TCW, Zhang H (2019b) Phosphorylation of TET2 by AMPK is indispensable in myogenic differentiation. Epigenetics Chromatin 12:32

72 Zhaolin Z, Jiaojiao C, Peng W, Yami L, Tingting Z, Jun T, Shiyuan W, Jinyan X, Dangheng W, Zhisheng J (2019) OxLDL induces vascular endothelial cell pyroptosis through miR-125a-5p/TET2 pathway. J Cell Physiol 234:7475–7491