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  • 제23권1호
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  • Pages.5.1-5.28
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  • 2023
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  • 1598-2629(pISSN)
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  • 2092-6685(eISSN)
대한면역학회 (The Korean Association of Immunobiologists)
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Transcriptional and Epigenetic Regulation of Context-Dependent Plasticity in T-Helper Lineages

  • Meyer J. Friedman (Department and School of Medicine, University of California) ;
  • Haram Lee (College of Pharmacy Korea University) ;
  • June-Yong Lee (Department of Microbiology and Immunology, Yonsei University College of Medicine) ;
  • Soohwan Oh (College of Pharmacy Korea University)
  • 투고 : 2023.01.01
  • 심사 : 2023.02.13
  • 발행 : 2023.02.28
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초록

Th cell lineage determination and functional specialization are tightly linked to the activation of lineage-determining transcription factors (TFs) that bind cis-regulatory elements. These lineage-determining TFs act in concert with multiple layers of transcriptional regulators to alter the epigenetic landscape, including DNA methylation, histone modification and threedimensional chromosome architecture, in order to facilitate the specific Th gene expression programs that allow for phenotypic diversification. Accumulating evidence indicates that Th cell differentiation is not as rigid as classically held; rather, extensive phenotypic plasticity is an inherent feature of T cell lineages. Recent studies have begun to uncover the epigenetic programs that mechanistically govern T cell subset specification and immunological memory. Advances in next generation sequencing technologies have allowed global transcriptomic and epigenomic interrogation of CD4+ Th cells that extends previous findings focusing on individual loci. In this review, we provide an overview of recent genome-wide insights into the transcriptional and epigenetic regulation of CD4+ T cell-mediated adaptive immunity and discuss the implications for disease as well as immunotherapies.

키워드

과제정보

June-Yong Lee is supported by a faculty research grant of Yonsei University College of Medicine (6-2022-0119), a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HV22C024901), and the Ministry of Education of the Republic of Korea and the National Research Foundation of Korea (2021R1C1C100691212). Soohwan Oh is supported by a Korea University Grant and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2022R1C1C101069911) and faculty research grant of Korea University (K2223251). Figures have been created with BioRender.

참고문헌

  1. Nair SJ, Suter T, Wang S, Yang L, Yang F, Rosenfeld MG. Transcriptional enhancers at 40: evolution of a viral DNA element to nuclear architectural structures. Trends Genet 2022;38:1019-1047.
  2. Zheng H, Xie W. The role of 3D genome organization in development and cell differentiation. Nat Rev Mol Cell Biol 2019;20:535-550.
  3. Bai L, Hao X, Keith J, Feng Y. DNA methylation in regulatory T cell differentiation and function: challenges and opportunities. Biomolecules 2022;12:1282.
  4. Waldman AD, Fritz JM, Lenardo MJ. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol 2020;20:651-668.
  5. Groser R, Cherkasky L, Chintala N, Adusumilli PS. Combination immunotherapy with CAR T cells and checkpoint blockade for the treatment of solid tumors. Cancer Cell 2019;36:471-482.
  6. Gun SY, Lee SW, Sieow JL, Wong SC. Targeting immune cells for cancer therapy. Redox Biol 2019;25:101174.
  7. Cavalli G, Heard E. Advances in epigenetics link genetics to the environment and disease. Nature 2019;571:489-499.
  8. Nakamura M, Gao Y, Dominguez AA, Qi LS. CRISPR technologies for precise epigenome editing. Nat Cell Biol 2021;23:11-22.
  9. Lyko F. The DNA methyltransferase family: a versatile toolkit for epigenetic regulation. Nat Rev Genet 2018;19:81-92.
  10. Allaman-Pillet N, Djemai A, Bonny C, Schorderet DF. Methylation status of CpG sites and methyl-CpG binding proteins are involved in the promoter regulation of the mouse Xist gene. Gene Expr 1998;7:61-73.
  11. Lister R, Pelizzola M, Dowen RH, Hawkins RD, Hon G, Tonti-Filippini J, Nery JR, Lee L, Ye Z, Ngo QM, et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 2009;462:315-322.
  12. Vaisvila R, Ponnaluri VK, Sun Z, Langhorst BW, Saleh L, Guan S, Dai N, Campbell MA, Sexton BS, Marks K, et al. Enzymatic methyl sequencing detects DNA methylation at single-base resolution from picograms of DNA. Genome Res 2021;31:1280-1289.
  13. Gouil Q, Keniry A. Latest techniques to study DNA methylation. Esays Biochem 2019;63:639-648.
  14. Maser DR, Berg AS, Freeman WM. Focused, high accuracy 5-methylcytosine quantitation with base resolution by benchtop next-generation sequencing. Epigenetics Chromatin 2013;6:33.
  15. Meyer CA, Liu XS. Identifying and mitigating bias in next-generation sequencing methods for chromatin biology. Nat Rev Genet 2014;15:709-721.
  16. Miraldi ER, Pokrovskii M, Watters A, Castro DM, De Veaux N, Hall JA, Lee JY, Ciofani M, Madar A, Carriero N, et al. Leveraging chromatin accesibility for transcriptional regulatory network inference in T Helper 17 Cells. Genome Res 2019;29:449-463.
  17. Hall JA, Pokrovskii M, Kroehling L, Kim BR, Kim SY, Wu L, Lee JY, Littman DR. Transcription factor RORα enforces stability of the Th17 cell effector program by binding to a Rorc cis-regulatory element. Immunity 2022;55:2027-2043.e9.
  18. Chen X, Cao G, Wu J, Wang X, Pan Z, Gao J, Tian Q, Xu L, Li Z, Hao Y, et al. The histone methyltransferase EZH2 primes the early differentiation of follicular helper T cells during acute viral infection. Cell Mol Immunol 2020;17:247-260.
  19. Hertweck A, Vila de Mucha M, Barber PR, Dagil R, Porter H, Ramos A, Lord GM, Jenner RG. The TH1 cell lineage-determining transcription factor T-bet suppreses TH2 gene expresion by redistributing GATA3 away from TH2 genes. Nucleic Acids Res 2022;50:4557-4573.
  20. DiSpirito JR, Zemmour D, Ramanan D, Cho J, Zilionis R, Klein AM, Benoist C, Mathis D. Molecular diversification of regulatory T cells in nonlymphoid tisues. Sci Immunol 2018;3:eaat5861.
  21. Johnson DS, Mortazavi A, Myers RM, Wold B. Genome-wide mapping of in vivo protein-DNA interactions. Science 2007;316:1497-1502.
  22. Kaya-Okur HS, Wu SJ, Codomo CA, Pledger ES, Bryson TD, Henikoff JG, Ahmad K, Henikoff S. CUT&Tag for efficient epigenomic profiling of small samples and single cells. Nat Commun 2019;10:1930.
  23. Skene PJ, Henikoff S. An efficient targeted nuclease strategy for high-resolution mapping of DNA binding sites. eLife 2017;6:6.
  24. Gopalan S, Wang Y, Harper NW, Garber M, Fazzio TG. Simultaneous profiling of multiple chromatin proteins in the same cells. Mol Cell 2021;81:4736-4746.e5.
  25. Ranzani V, Rosetti G, Panzeri I, Arrigoni A, Bonnal RJ, Curti S, Gruarin P, Provasi E, Sugliano E, Marconi M, et al. The long intergenic noncoding RNA landscape of human lymphocytes highlights the regulation of T cell differentiation by linc-MAF-4. Nat Immunol 2015;16:318-325.
  26. Taheri M, Barth DA, Kargl J, Rezaei O, Ghafouri-Fard S, Pichler M. Emerging role of non-coding RNAs in regulation of T-lymphocyte function. Front Immunol 2021;12:756042.
  27. Gibbons HR, Shaginurova G, Kim LC, Chapman N, Spurlock CF 3rd, Aune TM. Divergent lncRNA. Front Immunol 2018;9:2512.
  28. Zhao Y, Li H, Fang S, Kang Y, Wu W, Hao Y, Li Z, Bu D, Sun N, Zhang MQ, et al. NONCODE 2016: an informative and valuable data source of long non-coding RNAs. Nucleic Acids Res 2016;44:D203-D208.
  29. Wright C, Rajpurohit A, Burke EE, Williams C, Collado-Torres L, Kimos M, Brandon NJ, Cros AJ, Jaffe AE, Weinberger DR, et al. Comprehensive asesment of multiple biases in small RNA sequencing reveals significant differences in the performance of widely used methods. BMC Genomics 2019;20:513.
  30. Benesova S, Kubista M, Valihrach L. Small RNA-sequencing: approaches and considerations for miRNA analysis. Diagnostics (Basel) 2021;11:964.
  31. Wisink EM, Vihervaara A, Tippens ND, Lis JT. Nascent RNA analyses: tracking transcription and its regulation. Nat Rev Genet 2019;20:705-723.
  32. Lee JH, Xiong F, Li W. Enhancer RNAs in cancer: regulation, mechanisms and therapeutic potential. RNA Biol 2020;17:1550-1559.
  33. Oh S, Shao J, Mitra J, Xiong F, D'Antonio M, Wang R, Garcia-Basets I, Ma Q, Zhu X, Lee JH, et al. Enhancer release and retargeting activates disease-susceptibility genes. Nature 2021;595:735-740.
  34. Friedman MJ, Lee H, Kwon YC, Oh S. Dynamics of viral and host 3D genome structure upon infection. J Microbiol Biotechnol 2022;32:1515-1526.
  35. Cuartero S, Stik G, Stadhouders R. Three-dimensional genome organization in immune cell fate and function. Nat Rev Immunol 2022;
  36. Tian Y, Han C, Wei Z, Dong H, Shen X, Cui Y, Fu X, Tian Z, Wang S, Zhou J, et al. SOX-5 activates a novel RORγt enhancer to facilitate experimental autoimmune encephalomyelitis by promoting Th17 cell differentiation. Nat Commun 2021;12:481.
  37. Ren G, Jin W, Cui K, Rodrigez J, Hu G, Zhang Z, Larson DR, Zhao K. CTCF-mediated enhancer-promoter interaction is a critical regulator of cell-to-cell variation of gene expresion. Mol Cell 2017;67:1049-1058.e6.
  38. Chen Y, Chen C, Zhang Z, Liu CC, Johnson ME, Espinoza CA, Edsall LE, Ren B, Zhou XJ, Grant SF, et al. DNA binding by FOXP3 domain-swapped dimer suggests mechanisms of long-range chromosomal interactions. Nucleic Acids Res 2015;43:1268-1282.
  39. Hakim O, Sung MH, Nakayamada S, Vos TC, Baek S, Hager GL. Spatial congregation of STAT binding directs selective nuclear architecture during T-cell functional differentiation. Genome Res 2013;23:462-472.
  40. Isuree PD, Ng CP, Littman DR. Heritable gene regulation in the CD4:CD8 T cell lineage choice. Front Immunol 2017;8:291.
  41. Wei G, Wei L, Zhu J, Zang C, Hu-Li J, Yao Z, Cui K, Kanno Y, Roh TY, Watford WT, et al. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity 2009;30:155-167.
  42. Avni O, Lee D, Macian F, Szabo SJ, Glimcher LH, Rao A. T(H) cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes. Nat Immunol 2002;3:643-651.
  43. Melvin AJ, McGurn ME, Bort SJ, Gibson C, Lewis DB. Hypomethylation of the interferon-gamma gene correlates with its expresion by primary T-lineage cells. Eur J Immunol 1995;25:426-430.
  44. Thomas RM, Gamper CJ, Ladle BH, Powell JD, Wells AD. De novo DNA methylation is required to restrict T helper lineage plasticity. J Biol Chem 2012;287:22900-22909.
  45. Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations. Annu Rev Immunol 2010;28:445-489.
  46. Fields PE, Kim ST, Flavell RA. Cutting edge: changes in histone acetylation at the IL-4 and IFN-gamma loci accompany Th1/Th2 differentiation. J Immunol 2002;169:647-650.
  47. Vahedi G, Kanno Y, Furumoto Y, Jiang K, Parker SC, Erdos MR, Davis SR, Roychoudhuri R, Restifo NP, Gadina M, et al. Super-enhancers delineate disease-asociated regulatory nodes in T cells. Nature 2015;520:558-562.
  48. Lee S, Kim J, Min H, Seong RH. RORγt-driven TH17 cell differentiation requires epigenetic control by the Swi/Snf chromatin remodeling complex. iScience 2020;23:101106.
  49. Kanno Y, Vahedi G, Hirahara K, Singleton K, O'Shea JJ. Transcriptional and epigenetic control of T helper cell specification: molecular mechanisms underlying commitment and plasticity. Annu Rev Immunol 2012;30:707-731.
  50. Vahedi G, Takahashi H, Nakayamada S, Sun HW, Sartorelli V, Kanno Y, O'Shea JJ. STATs shape the active enhancer landscape of T cell populations. Cell 2012;151:981-993.
  51. Lazarevic V, Glimcher LH, Lord GM. T-bet: a bridge between innate and adaptive immunity. Nat Rev Immunol 2013;13:777-789.
  52. Hermann-Kleiter N, Baier G. NFAT pulls the strings during CD4+ T helper cell effector functions. Blood 2010;115:2989-2997.
  53. Placek K, Coffre M, Maiella S, Bianchi E, Rogge L. Genetic and epigenetic networks controlling T helper 1 cell differentiation. Immunology 2009;127:155-162.
  54. Li Q, Zou J, Wang M, Ding X, Chepelev I, Zhou X, Zhao W, Wei G, Cui J, Zhao K, et al. Critical role of histone demethylase Jmjd3 in the regulation of CD4+ T-cell differentiation. Nat Commun 2014;5:5780.
  55. Zhu J, Jankovic D, Oler AJ, Wei G, Sharma S, Hu G, Guo L, Yagi R, Yamane H, Punkosdy G, et al. The transcription factor T-bet is induced by multiple pathways and prevents an endogenous Th2 cell program during Th1 cell responses. Immunity 2012;37:660-673.
  56. Hadjur S, Williams LM, Ryan NK, Cobb BS, Sexton T, Fraser P, Fisher AG, Merkenschlager M. Cohesins form chromosomal cis-interactions at the developmentally regulated IFNG locus. Nature 2009;460:410-413.
  57. Walker JA, McKenzie AN. TH2 cell development and function. Nat Rev Immunol 2018;18:121-133.
  58. Wei L, Vahedi G, Sun HW, Watford WT, Takatori H, Ramos HL, Takahashi H, Liang J, Gutierrez-Cruz G, Zang C, et al. Discrete roles of STAT4 and STAT6 transcription factors in tuning epigenetic modifications and transcription during T helper cell differentiation. Immunity 2010;32:840-851.
  59. Onodera A, Kokubo K, Nakayama T. Epigenetic and transcriptional regulation in the induction, maintenance, heterogeneity, and recall-response of effector and memory Th2 cells. Front Immunol 2018;9:2929.
  60. Ho IC, Miaw SC. Regulation of IL-4 expresion in immunity and diseases. Adv Exp Med Biol 2016;941:31-77.
  61. Fang D, Cui K, Hu G, Gurram RK, Zhong C, Oler AJ, Yagi R, Zhao M, Sharma S, Liu P, et al. Bcl11b, a novel GATA3-interacting protein, suppreses Th1 while limiting Th2 cell differentiation. J Exp Med 2018;215:1449-1462.
  62. Hosokawa H, Kato M, Tohyama H, Tamaki Y, Endo Y, Kimura MY, Tumes DJ, Motohashi S, Matsumoto M, Nakayama KI, et al. Methylation of Gata3 protein at Arg-261 regulates transactivation of the Il5 gene in T helper 2 cells. J Biol Chem 2015;290:13095-13103.
  63. Nakayama T, Hirahara K, Onodera A, Endo Y, Hosokawa H, Shinoda K, Tumes DJ, Okamoto Y. Th2 cells in health and disease. Annu Rev Immunol 2017;35:53-84.
  64. Spilianakis CG, Lalioti MD, Town T, Lee GR, Flavell RA. Interchromosomal asociations between alternatively expresed loci. Nature 2005;435:637-645.
  65. Chen HV, et al. Deletion mapping of regulatory elements for GATA3 reveals a distal T helper 2 cell enhancer involved in allergic diseases. Preprint at https://www.biorxiv.org/content/10.1101/2022.05.24.493112v1.
  66. Akuzum B, Lee JY. Context-dependent regulation of type17 immunity by microbiota at the intestinal barrier. Immune Netw 2022;22:e46.
  67. Capone A, Volpe E. Transcriptional regulators of T helper 17 cell differentiation in health and autoimmune diseases. Front Immunol 2020;11:348.
  68. Chang D, Xing Q, Su Y, Zhao X, Xu W, Wang X, Dong C. The conserved non-coding sequences CNS6 and CNS9 control cytokine-induced Rorc transcription during T helper 17 cell differentiation. Immunity 2020;53:614-626.e4.
  69. Kumar R, Theis AL, Venuprasad K. RORγt protein modifications and IL-17-mediated inflammation. Trends Immunol 2021;42:1037-1050.
  70. Olatunde AC, Hale JS, Lamb TJ. Cytokine-skewed Tfh cells: functional consequences for B cell help. Trends Immunol 2021;42:536-550.
  71. Jeon YH, Choi YS. Follicular helper T (Tfh) cells in autoimmune diseases and allograft rejection. Immune Netw 2016;16:219-232.
  72. Choi YS, Yang JA, Crotty S. Dynamic regulation of Bcl6 in follicular helper CD4 T (Tfh) cells. Curr Opin Immunol 2013;25:366-372.
  73. Choi YS, Eto D, Yang JA, Lao C, Crotty S. Cutting edge: STAT1 is required for IL-6-mediated Bcl6 induction for early follicular helper cell differentiation. J Immunol 2013;190:3049-3053.
  74. Nakayamada S, Kanno Y, Takahashi H, Jankovic D, Lu KT, Johnson TA, Sun HW, Vahedi G, Hakim O, Handon R, et al. Early Th1 cell differentiation is marked by a Tfh cell-like transition. Immunity 2011;35:919-931.
  75. Choi J, Crotty S. Bcl6-mediated transcriptional regulation of follicular helper T cells (TFH). Trends Immunol 2021;42:336-349.
  76. Stone EL, Pepper M, Katayama CD, Kerdiles YM, Lai CY, Emslie E, Lin YC, Yang E, Goldrath AW, Li MO, et al. ICOS coreceptor signaling inactivates the transcription factor FOXO1 to promote Tfh cell differentiation. Immunity 2015;42:239-251.
  77. Choi J, Diao H, Faliti CE, Truong J, Rosi M, Belanger S, Yu B, Goldrath AW, Pipkin ME, Crotty S. Bcl-6 is the nexus transcription factor of T follicular helper cells via represor-of-represor circuits. Nat Immunol 2020;21:777-789.
  78. Bunting KL, Soong TD, Singh R, Jiang Y, Beguelin W, Poloway DW, Swed BL, Hatzi K, Reisacher W, Teater M, et al. Multi-tiered reorganization of the genome during B cell affinity maturation anchored by a germinal center-specific locus control region. Immunity 2016;45:497-512.
  79. Lee W, Lee GR. Transcriptional regulation and development of regulatory T cells. Exp Mol Med 2018;50:e456.
  80. Hagihara Y, Yoshimatsu Y, Mikami Y, Takada Y, Mizuno S, Kanai T. Epigenetic regulation of T helper cells and intestinal pathogenicity. Semin Immunopathol 2019;41:379-399.
  81. Someya K, Nakatsukasa H, Ito M, Kondo T, Tateda KI, Akanuma T, Koya I, Sanosaka T, Kohyama J, Tsukada YI, et al. Improvement of Foxp3 stability through CNS2 demethylation by TET enzyme induction and activation. Int Immunol 2017;29:365-375.
  82. Kawakami R, Kitagawa Y, Chen KY, Arai M, Ohara D, Nakamura Y, Yasuda K, Osaki M, Mikami N, Lareau CA, et al. Distinct Foxp3 enhancer elements coordinate development, maintenance, and function of regulatory T cells. Immunity 2021;54:947-961.e8.
  83. Deng G, Song X, Greene MI. FoxP3 in Treg cell biology: a molecular and structural perspective. Clin Exp Immunol 2020;199:255-262.
  84. Dong Y, Yang C, Pan F. Post-translational regulations of Foxp3 in Treg cells and their therapeutic applications. Front Immunol 2021;12:626172.
  85. Rudra D, deRoos P, Chaudhry A, Niec RE, Arvey A, Samstein RM, Leslie C, Shaffer SA, Goodlett DR, Rudensky AY. Transcription factor Foxp3 and its protein partners form a complex regulatory network. Nat Immunol 2012;13:1010-1019.
  86. Colamatteo A, Carbone F, Bruzzaniti S, Galgani M, Fusco C, Maniscalco GT, Di Rella F, de Candia P, De Rosa V. Molecular mechanisms controlling foxp3 expresion in health and autoimmunity: from epigenetic to post-translational regulation. Front Immunol 2020;10:3136.
  87. Ramirez RN, Chowdhary K, Leon J, Mathis D, Benoist C. FoxP3 asociates with enhancer-promoter loops to regulate Treg-specific gene expresion. Sci Immunol 2022;7:eabj9836.
  88. Kwon HK, Chen HM, Mathis D, Benoist C. Different molecular complexes that mediate transcriptional induction and represion by FoxP3. Nat Immunol 2017;18:1238-1248.
  89. Yoshida H, Lareau CA, Ramirez RN, Rose SA, Maier B, Wroblewska A, Desland F, Chudnovskiy A, Mortha A, Dominguez C, et al. The cis-regulatory atlas of the mouse immune system. Cell 2019;176:897-912.e20.
  90. Peine M, Rausch S, Helmstetter C, Frohlich A, Hegazy AN, Kuhl AA, Grevelding CG, Hofer T, Hartmann S, Lohning M. Stable T-bet(+)GATA-3(+) Th1/Th2 hybrid cells arise in vivo, can develop directly from naive precursors, and limit immunopathologic inflammation. PLoS Biol 2013;11:e1001633.
  91. Burt P, Peine M, Peine C, Borek Z, Serve S, Flosdorf M, Hegazy AN, Hofer T, Lohning M, Thurley K. Disecting the dynamic transcriptional landscape of early T helper cell differentiation into Th1, Th2, and Th1/2 hybrid cells. Front Immunol 2022;13:928018.
  92. Ghoreschi K, Laurence A, Yang XP, Tato CM, McGeachy MJ, Konkel JE, Ramos HL, Wei L, Davidson TS, Bouladoux N, et al. Generation of pathogenic T(H)17 cells in the absence of TGF-β signalling. Nature 2010;467:967-971.
  93. Cosmi L, Maggi L, Santarlasci V, Capone M, Cardilicchia E, Frosali F, Querci V, Angeli R, Matucci A, Fambrini M, et al. Identification of a novel subset of human circulating memory CD4(+) T cells that produce both IL-17A and IL-4. J Allergy Clin Immunol 2010;125:222-230.e1-4.
  94. Mirlekar B. Co-expresion of master transcription factors determines CD4+ T cell plasticity and functions in auto-inflammatory diseases. Immunol Lett 2020;222:58-66.
  95. Harbour SN, Maynard CL, Zindl CL, Schoeb TR, Weaver CT. Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis. Proc Natl Acad Sci U S A 2015;112:7061-7066.
  96. Yang BH, Floes S, Hagemann S, Deyneko IV, Groebe L, Pezoldt J, Sparwaser T, Lochner M, Huehn J. Development of a unique epigenetic signature during in vivo Th17 differentiation. Nucleic Acids Res 2015;43:1537-1548.
  97. Obermajer N, Popp FC, Soeder Y, Haarer J, Geisler EK, Schlitt HJ, Dahlke MH. Conversion of Th17 into IL-17A(neg) regulatory T cells: a novel mechanism in prolonged allograft survival promoted by mesenchymal stem cell-supported minimized immunosuppresive therapy. J Immunol 2014;193:4988-4999.
  98. Mazzoni A, Santarlasci V, Maggi L, Capone M, Rosi MC, Querci V, De Palma R, Chang HD, Thiel A, Cimaz R, et al. Demethylation of the RORC2 and IL17A in human CD4+ T lymphocytes defines Th17 origin of nonclasic Th1 cells. J Immunol 2015;194:3116-3126.
  99. Mukasa R, Balasubramani A, Lee YK, Whitley SK, Weaver BT, Shibata Y, Crawford GE, Hatton RD, Weaver CT. Epigenetic instability of cytokine and transcription factor gene loci underlies plasticity of the T helper 17 cell lineage. Immunity 2010;32:616-627.
  100. Lee YK, Turner H, Maynard CL, Oliver JR, Chen D, Elson CO, Weaver CT. Late developmental plasticity in the T helper 17 lineage. Immunity 2009;30:92-107.
  101. Zheng W, Flavell RA. The transcription factor GATA-3 is necesary and sufficient for Th2 cytokine gene expresion in CD4 T cells. Cell 1997;89:587-596.
  102. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003;4:330-336.
  103. Bam M, Chintala S, Fetcko K, Williamsen BC, Siraj S, Liu S, Wan J, Xuei X, Liu Y, Leibold AT, et al. Genome wide DNA methylation landscape reveals glioblastoma's influence on epigenetic changes in tumor infiltrating CD4+ T cells. Oncotarget 2021;12:967-981.
  104. Wang D, Quiros J, Mahuron K, Pai CC, Ranzani V, Young A, Silveria S, Harwin T, Abnousian A, Pagani M, et al. Targeting EZH2 reprograms intratumoral regulatory T cells to enhance cancer immunity. Cell Reports 2018;23:3262-3274.
  105. Weisenberger DJ, Lakshminarasimhan R, Liang G. The role of DNA methylation and DNA methyltransferases in cancer. Adv Exp Med Biol 2022;1389:317-348.
  106. Yu X, Yuan Z, Yang Z, Chen D, Kim T, Cui Y, Luo Q, Liu Z, Yang Z, Fan X, et al. The novel long noncoding RNA u50535 promotes colorectal cancer growth and metastasis by regulating CCL20. Cell Death Dis 2018;9:751.
  107. Vitiello GA, Miller G. Targeting the interleukin-17 immune axis for cancer immunotherapy. J Exp Med 2020;217:e20190456.
  108. Sasidharan Nair V, Heredia M, Samsom J, Huehn J. Impact of gut microenvironment on epigenetic signatures of intestinal T helper cell subsets. Immunol Lett 2022;246:27-36.
  109. Yang P, Qian FY, Zhang MF, Xu AL, Wang X, Jiang BP, Zhou LL. Th17 cell pathogenicity and plasticity in rheumatoid arthritis. J Leukoc Biol 2019;106:1233-1240.
  110. Morrison PJ, Bending D, Fouser LA, Wright JF, Stockinger B, Cooke A, Kullberg MC. Th17-cell plasticity in Helicobacter hepaticus-induced intestinal inflammation. Mucosal Immunol 2013;6:1143-1156.
  111. Fu SH, Chien MW, Hsu CY, Liu YW, Sytwu HK. Interplay between cytokine circuitry and transcriptional regulation shaping helper T cell pathogenicity and plasticity in inflammatory bowel disease. Int J Mol Sci 2020;21:3379.
  112. Belpaire A, van Geel N, Speeckaert R. From IL-17 to IFN-γ in inflammatory skin disorders: is transdifferentiation a potential treatment target? Front Immunol 2022;13:932265.
  113. Bhaskaran N, Liu Z, Saravanamuthu SS, Yan C, Hu Y, Dong L, Zelenka P, Zheng L, Bletsos V, Harris R, et al. Identification of Casz1 as a regulatory protein controlling T helper cell differentiation, inflammation, and immunity. Front Immunol 2018;9:184.
  114. Brucklacher-Waldert V, Ferreira C, Innocentin S, Kamdar S, Withers DR, Kullberg MC, Veldhoen M. Tbet or continued RORγt expresion is not required for Th17-asociated immunopathology. J Immunol 2016;196:4893-4904.
  115. Quandt J, Arnovitz S, Haghi L, Woehlk J, Mohsin A, Okoreeh M, Mathur PS, Emmanuel AO, Osman A, Krishnan M, et al. Wnt-β-catenin activation epigenetically reprograms Treg cells in inflammatory bowel disease and dysplastic progresion. Nat Immunol 2021;22:471-484.
  116. Saxena V, Lakhan R, Iyyathurai J, Bromberg JS. Mechanisms of exTreg induction. Eur J Immunol 2021;51:1956-1967.
  117. Tseng WY, Huang YS, Clanchy F, McNamee K, Perocheau D, Ogbechi J, Luo SF, Feldmann M, McCann FE, Williams RO. TNF receptor 2 signaling prevents DNA methylation at the Foxp3 promoter and prevents pathogenic conversion of regulatory T cells. Proc Natl Acad Sci U S A 2019;116:21666-21672.
  118. Xia M, Liu J, Liu S, Chen K, Lin H, Jiang M, Xu X, Xue Y, Liu W, Gu Y, et al. Ash1l and lnc-Smad3 coordinate Smad3 locus accesibility to modulate iTreg polarization and T cell autoimmunity. Nat Commun 2017;8:15818.
  119. Ganesan A, Arimondo PB, Rots MG, Jeronimo C, Berdasco M. The timeline of epigenetic drug discovery: from reality to dreams. Clin Epigenetics 2019;11:174.
  120. Deaton AM, Bird A. CpG islands and the regulation of transcription. Genes Dev 2011;25:1010-1022.
  121. Yang X, Han H, De Carvalho DD, Lay FD, Jones PA, Liang G. Gene body methylation can alter gene expresion and is a therapeutic target in cancer. Cancer Cell 2014;26:577-590.
  122. Heyn H, Vidal E, Ferreira HJ, Vizoso M, Sayols S, Gomez A, Moran S, Boque-Sastre R, Guil S, Martinez- Cardus A, et al. Epigenomic analysis detects aberrant super-enhancer DNA methylation in human cancer. Genome Biol 2016;17:11.
  123. Cabezon M, Malinverni R, Bargay J, Xicoy B, Marce S, Garrido A, Tormo M, Arenillas L, Coll R, Borras J, et al. Different methylation signatures at diagnosis in patients with high-risk myelodysplastic syndromes and secondary acute myeloid leukemia predict azacitidine response and longer survival. Clin Epigenetics 2021;13:9.
  124. Diesch J, Zwick A, Garz AK, Palau A, Buschbeck M, Gotze KS. A clinical-molecular update on azanucleoside-based therapy for the treatment of hematologic cancers. Clin Epigenetics 2016;8:71.
  125. Pappalardi MB, Keenan K, Cockerill M, Kellner WA, Stowell A, Sherk C, Wong K, Pathuri S, Briand J, Steidel M, et al. Discovery of a first-in-clas reversible DNMT1-selective inhibitor with improved tolerability and efficacy in acute myeloid leukemia. Nat Can 2021;2:1002-1017.
  126. Ebelt ND, Zuniga E, Johnson BL, Diamond DJ, Manuel ER. 5-Azacytidine potentiates anti-tumor immunity in a model of pancreatic ductal adenocarcinoma. Front Immunol 2020;11:538.
  127. Chiappinelli KB, Strisel PL, Desrichard A, Li H, Henke C, Akman B, Hein A, Rote NS, Cope LM, Snyder A, et al. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell 2015;162:974-986.
  128. Lemonnier F, Dupuis J, Sujobert P, Tournillhac O, Cheminant M, Sarkozy C, Pelletier L, Marcais A, Robe C, Fataccioli V, et al. Treatment with 5-azacytidine induces a sustained response in patients with angioimmunoblastic T-cell lymphoma. Blood 2018;132:2305-2309.
  129. Sanchez-Abarca LI, Gutierrez-Cosio S, Santamaria C, Caballero-Velazquez T, Blanco B, Herrero-Sanchez C, Garcia JL, Carrancio S, Hernandez-Campo P, Gonzalez FJ, et al. Immunomodulatory effect of 5-azacytidine (5-azaC): potential role in the transplantation setting. Blood 2010;115:107-121.
  130. Bondarev AD, Attwood MM, Jonson J, Chubarev VN, Tarasov VV, Schioth HB. Recent developments of HDAC inhibitors: emerging indications and novel molecules. Br J Clin Pharmacol 2021;87:4577-4597.
  131. Zhang F, Zhou X, DiSpirito JR, Wang C, Wang Y, Shen H. Epigenetic manipulation restores functions of defective CD8+ T cells from chronic viral infection. Mol Ther 2014;22:1698-1706.
  132. Woods DM, Sodre AL, Villagra A, Sarnaik A, Sotomayor EM, Weber J. HDAC inhibition upregulates PD-1 ligands in melanoma and augments immunotherapy with PD-1 blockade. Cancer Immunol Res 2015;3:1375-1385.
  133. Lange UC, Verdikt R, Ait-Ammar A, Van Lint C. Epigenetic crostalk in chronic infection with HIV-1. Semin Immunopathol 2020;42:187-200.
  134. Abner E, Jordan A. HIV "shock and kill" therapy: in need of revision. Antiviral Res 2019;166:19-34.
  135. Rezai-Zadeh K, Gate D, Town T. CNS infiltration of peripheral immune cells: D-Day for neurodegenerative disease? J Neuroimmune Pharmacol 2009;4:462-475.
  136. Andrieu G, Belkina AC, Denis GV. Clinical trials for BET inhibitors run ahead of the science. Drug Discov Today Technol 2016;19:45-50.
  137. Shorstova T, Foulkes WD, Witcher M. Achieving clinical succes with BET inhibitors as anti-cancer agents. Br J Cancer 2021;124:1478-1490.
  138. Mele DA, Salmeron A, Ghosh S, Huang HR, Bryant BM, Lora JM. BET bromodomain inhibition suppreses TH17-mediated pathology. J Exp Med 2013;210:2181-2190.
  139. Ferreira de Freitas R, Ivanochko D, Schapira M. Methyltransferase inhibitors: competing with, or exploiting the bound cofactor. Molecules 2019;24:4492.
  140. Feng FY, de Bono JS, Rubin MA, Knudsen KE. Chromatin to clinic: the molecular rationale for PARP1 inhibitor function. Mol Cell 2015;58:925-934.
  141. Rose M, Burges JT, O'Byrne K, Richard DJ, Bolderson E. PARP inhibitors: clinical relevance, mechanisms of action and tumor resistance. Front Cell Dev Biol 2020;8:564601.
  142. Nasta F, Laudisi F, Sambucci M, Rosado MM, Pioli C. Increased Foxp3+ regulatory T cells in poly(ADPRibose) polymerase-1 deficiency. J Immunol 2010;184:3470-3477.
  143. Luo X, Nie J, Wang S, Chen Z, Chen W, Li D, Hu H, Li B. Poly(ADP-ribosyl)ation of FOXP3 protein mediated by PARP-1 protein regulates the function of regulatory T cells. J Biol Chem 2015;290:28675-28682.
  144. Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 2015;348:62-68.
  145. Zhao Z, Melenhorst JJ. Adaptable leukemia cells resisting CAR T-cell attack via B-cell activation. Cancer Immunol Res 2022;10:1040.
  146. Rurik JG, Epstein JA. Uniting disciplines to develop therapeutics: targeted mRNA lipid nanoparticles reprogram the immune system in vivo to treat heart disease. DNA Cell Biol 2022;41:539-543.
  147. Raffin C, Vo LT, Bluestone JA. Treg cell-based therapies: challenges and perspectives. Nat Rev Immunol 2020;20:158-172.
  148. Gilbert LA, Larson MH, Morsut L, Liu Z, Brar GA, Torres SE, Stern-Ginosar N, Brandman O, Whitehead EH, Doudna JA, et al. CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes. Cell 2013;154:442-451.
  149. Konermann S, Brigham MD, Trevino AE, Joung J, Abudayyeh OO, Barcena C, Hsu PD, Habib N, Gootenberg JS, Nishimasu H, et al. Genome-scale transcriptional activation by an engineered CRISPRCas9 complex. Nature 2015;517:583-588.