Skip to main navigation menu Skip to main content Skip to site footer
##common.pageHeaderLogo.altText##

Review article: Biomedical intelligence

Vol. 145 No. 4344 (2015)

Epigenetics of T lymphocytes in health and disease

  • Cristina Leoni
  • Lucia Vincenzetti
  • Stefan Emming
  • Silvia Monticelli
DOI
https://doi.org/10.4414/smw.2015.14191
Cite this as:
Swiss Med Wkly. 2015;145:w14191
Published
18.10.2015

Summary

The risk of developing autoimmune diseases depends on both genetic and environmental factors, with epigenetic mechanisms of regulation potentially translating environmental cues into stable modifications in gene expression. Such stable memory of a functional state has been deciphered into a number of molecular mechanisms that collectively define the epigenetic status of a cell. In recent years, it has become increasingly clear that epigenetic modifications are highly dynamic and are able to adapt to the changing environment, with important impact on the onset and development of a number of diseases. Here, we describe some of the epigenetic mechanisms of regulation of cellular functional states in T lymphocytes, with a particular focus on DNA methylation. We will also discuss current knowledge on the role of epigenetics in autoimmunity and consider open questions in the field.

References

  1. Bird A. Perceptions of epigenetics. Nature. 2007;447(7143):396–8.
  2. Berger SL, et al. An operational definition of epigenetics. Genes Dev. 2009;23(7):781–3.
  3. Monticelli S, Natoli G. Short-term memory of danger signals and environmental stimuli in immune cells. Nat Immunol. 2013;14(8):777–84.
  4. Natoli G. Maintaining cell identity through global control of genomic organization. Immunity. 2010;33(1):12–24.
  5. Cullen SM, et al. Hematopoietic stem cell development: an epigenetic journey. Curr Top Dev Biol. 2014;107:39–75.
  6. Okano M, et al. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell. 1999;99(3):247–57.
  7. Mayle A, et al. Dnmt3a loss predisposes murine hematopoietic stem cells to malignant transformation. Blood. 2015;125(4):629–38.
  8. Celik H, et al. Enforced differentiation of Dnmt3a-null bone marrow leads to failure with c-Kit mutations driving leukemic transformation. Blood. 2015;125(4):619–28.
  9. Xu GL, et al. Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature. 1999;402(6758):187–91.
  10. Dawson MA, Kouzarides T. Cancer epigenetics: from mechanism to therapy. Cell. 2012;150(1):12–27.
  11. Baubec T, et al. Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation. Nature. 2015;520(7546):243–7.
  12. Guo X, et al. Structural insight into autoinhibition and histone H3-induced activation of DNMT3A. Nature. 2015;517(7536):640–4.
  13. Ooi SK, et al. DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature. 2007;448(7154):714–7.
  14. Rishi V, et al. CpG methylation of half-CRE sequences creates C/EBPalpha binding sites that activate some tissue-specific genes. Proc Natl Acad Sci U S A. 2010;107(47):20311–6.
  15. Spruijt CG, et al. Dynamic readers for 5-(hydroxy)methylcytosine and its oxidized derivatives. Cell. 2013;152(5):1146–59.
  16. Spruijt CG, Vermeulen M. DNA methylation: old dog, new tricks? Nat Struct Mol Biol. 2014;21(11):949–54.
  17. Baubec T, Schubeler D. Genomic patterns and context specific interpretation of DNA methylation. Curr Opin Genet Dev. 2014;25:85–92.
  18. Jones PA. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet. 2012;13(7):484–92.
  19. Jeltsch A. Molecular biology. Phylogeny of methylomes. Science. 2010;328(5980):837–8.
  20. Heyn H, Esteller M. An Adenine Code for DNA: A Second Life for N6-Methyladenine. Cell. 2015;161(4):710–3.
  21. Zemach A, et al. Genome-wide evolutionary analysis of eukaryotic DNA methylation. Science. 2010;328(5980):916–9.
  22. Feng S, et al. Conservation and divergence of methylation patterning in plants and animals. Proc Natl Acad Sci U S A. 2010;107(19):8689–94.
  23. Yearim A, et al. HP1 is involved in regulating the global impact of DNA methylation on alternative splicing. Cell Rep. 2015;10(7):1122–34.
  24. Challen GA, et al. Dnmt3a is essential for hematopoietic stem cell differentiation. Nat Genet. 2012;44(1):23–31.
  25. Challen GA, et al. Dnmt3a and Dnmt3b have overlapping and distinct functions in hematopoietic stem cells. Cell Stem Cell. 2014;15(3):350–64.
  26. Pastor WA, Aravind L, Rao A. TETonic shift: biological roles of TET proteins in DNA demethylation and transcription. Nat Rev Mol Cell Biol. 2013;14(6):341–56.
  27. Tahiliani M, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009;324(5929):930–5.
  28. Ito S, et al. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science. 2011;333(6047):1300–3.
  29. Ko M, et al. Ten-Eleven-Translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice. Proc Natl Acad Sci U S A. 2011;108(35):14566–71.
  30. Moran-Crusio K, et al. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell. 2011;20(1):11–24.
  31. Li Z, et al. Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies. Blood. 2011;118(17):4509–18.
  32. Cimmino L, et al. TET family proteins and their role in stem cell differentiation and transformation. Cell Stem Cell. 2011;9(3):193–204.
  33. Quivoron C, et al. TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis. Cancer Cell. 2011;20(1):25–38.
  34. Huang Y, et al. The behaviour of 5-hydroxymethylcytosine in bisulfite sequencing. PLoS One. 2010;5(1):e8888.
  35. Simmons SB, et al. Modeling the heterogeneity of multiple sclerosis in animals. Trends Immunol. 2013;34(8):410–22.
  36. Sospedra M, Martin R. Immunology of multiple sclerosis. Annu Rev Immunol. 2005;23:683–747.
  37. Peters A, Lee Y, Kuchroo VK. The many faces of Th17 cells. Curr Opin Immunol. 2011;23(6):702–6.
  38. Kersh EN, et al. Rapid demethylation of the IFN-gamma gene occurs in memory but not naive CD8 T cells. J Immunol. 2006;176(7):4083–93.
  39. Makar KW, et al. Active recruitment of DNA methyltransferases regulates interleukin 4 in thymocytes and T cells. Nat Immunol. 2003;4(12):1183–90.
  40. Bruniquel D, Schwartz RH. Selective, stable demethylation of the interleukin-2 gene enhances transcription by an active process. Nat Immunol. 2003;4(3):235–40.
  41. Gamper CJ, et al. Identification of DNA methyltransferase 3a as a T cell receptor-induced regulator of Th1 and Th2 differentiation. J Immunol. 2009;183(4):2267–76.
  42. Lee PP, et al. A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival. Immunity. 2001;15(5):763–74.
  43. Yu Q, et al. DNA methyltransferase 3a limits the expression of interleukin-13 in T helper 2 cells and allergic airway inflammation. Proc Natl Acad Sci U S A. 2012;109(2):541–6.
  44. Hutchins AS, et al. Gene silencing quantitatively controls the function of a developmental trans-activator. Mol Cell. 2002;10(1):81–91.
  45. Makar KW, Wilson CB. DNA methylation is a nonredundant repressor of the Th2 effector program. J Immunol. 2004;173(7):4402–6.
  46. Scharer CD, et al. Global DNA methylation remodeling accompanies CD8 T cell effector function. J Immunol. 2013;191(6):3419–29.
  47. Hashimoto S, et al. Coordinated changes in DNA methylation in antigen-specific memory CD4 T cells. J Immunol. 2013;190(8):4076–91.
  48. Ichiyama K, et al. The Methylcytosine Dioxygenase Tet2 Promotes DNA Demethylation and Activation of Cytokine Gene Expression in T Cells. Immunity. 2015.
  49. Lal G, Bromberg JS. Epigenetic mechanisms of regulation of Foxp3 expression. Blood. 2009;114(18):3727–35.
  50. Feng Y, et al. Control of the inheritance of regulatory T cell identity by a cis element in the Foxp3 locus. Cell. 2014 ;158(4):749–63.
  51. Polansky JK, et al. DNA methylation controls Foxp3 gene expression. Eur J Immunol. 2008;38(6):1654–63.
  52. Wang L, et al. Foxp3+ T-regulatory cells require DNA methyltransferase 1 expression to prevent development of lethal autoimmunity. Blood. 2013;121(18):3631–9.
  53. International Multiple Sclerosis Genetics, C., et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 2011;476(7359):214–9.
  54. Willer CJ, et al. Twin concordance and sibling recurrence rates in multiple sclerosis. Proc Natl Acad Sci U S A. 2003;100(22):12877–82.
  55. Ballestar E, Esteller M, Richardson BC. The epigenetic face of systemic lupus erythematosus. J Immunol. 2006;176(12):7143–7.
  56. Brodin P, et al. Variation in the human immune system is largely driven by non-heritable influences. Cell. 2015;160(1-2):37–47.
  57. Baranzini SE, et al. Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis. Nature. 2010;464(7293):1351–6.
  58. Farh KK, et al. Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature. 2015;518(7539):337–43.
  59. Rakyan VK, et al. Identification of type 1 diabetes-associated DNA methylation variable positions that precede disease diagnosis. PLoS Genet. 2011;7(9): p. e1002300.
  60. Quddus J, et al. Treating activated CD4+ T cells with either of two distinct DNA methyltransferase inhibitors, 5-azacytidine or procainamide, is sufficient to cause a lupus-like disease in syngeneic mice. J Clin Invest. 1993;92(1):38–53.
  61. Hedrich CM, et al. Stat3 promotes IL-10 expression in lupus T cells through trans-activation and chromatin remodeling. Proc Natl Acad Sci U S A. 2014;111(37):13457–62.
  62. Rauen T, et al. cAMP-responsive element modulator (CREM)alpha protein induces interleukin 17A expression and mediates epigenetic alterations at the interleukin-17A gene locus in patients with systemic lupus erythematosus. J Biol Chem. 2011;286(50):43437–46.
  63. Picascia A, et al. Epigenetic control of autoimmune diseases: from bench to bedside. Clin Immunol. 2015;157(1):1–15.
  64. Glant TT, Mikecz K, Rauch TA. Epigenetics in the pathogenesis of rheumatoid arthritis. BMC Med. 2014;12:35.
  65. Esteller M. Epigenetics in cancer. N Engl J Med. 2008;358(11):1148–59.
  66. Lian CG, et al. Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma. Cell. 2012;150(6):1135–46.
  67. Leoni C, et al. Reduced DNA methylation and hydroxymethylation in patients with systemic mastocytosis. Eur J Haematol. 2015.
  68. Ko M, et al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature. 2010;468(7325):839–43.
  69. Smith ZD, Meissner A. DNA methylation: roles in mammalian development. Nat Rev Genet. 2013;14(3):204–20.
  70. Issa JP. Aging and epigenetic drift: a vicious cycle. J Clin Invest. 2014;124(1):24–9.
  71. Maegawa S, et al. Widespread and tissue specific age-related DNA methylation changes in mice. Genome Res. 2010;20(3):332–40.
  72. Niwa T, et al. Inflammatory processes triggered by Helicobacter pylori infection cause aberrant DNA methylation in gastric epithelial cells. Cancer Res. 2010;70(4):1430–40.
  73. Monticelli S. MicroRNAs in T helper cell differentiation and plasticity. Semin Immunol. 2013;25(4):291–8.
  74. Pauley KM, Cha S, Chan EK. MicroRNA in autoimmunity and autoimmune diseases. J Autoimmun. 2009;32(3-4):189–94.
  75. Wei B, Pei G. microRNAs: critical regulators in Th17 cells and players in diseases. Cell Mol Immunol. 2010;7(3):175–81.
  76. Pan W, et al. MicroRNA-21 and microRNA-148a contribute to DNA hypomethylation in lupus CD4+ T cells by directly and indirectly targeting DNA methyltransferase 1. J Immunol. 2010;184(12):6773–81.
  77. Murugaiyan G, et al. Silencing microRNA-155 ameliorates experimental autoimmune encephalomyelitis. J Immunol. 2011;187(5):2213–21.
  78. Smith KM, et al. miR-29ab1 deficiency identifies a negative feedback loop controlling Th1 bias that is dysregulated in multiple sclerosis. J Immunol. 2012;189(4):1567–76.
  79. Du C, et al. MicroRNA miR-326 regulates TH-17 differentiation and is associated with the pathogenesis of multiple sclerosis. Nat Immunol. 2009;10(12):1252–9.
  80. Zhu E, et al. miR-20b suppresses Th17 differentiation and the pathogenesis of experimental autoimmune encephalomyelitis by targeting RORgammat and STAT3. J Immunol. 2014;192(12):5599–609.
  81. Lindberg RL, et al. Altered expression of miR-17-5p in CD4+ lymphocytes of relapsing-remitting multiple sclerosis patients. Eur J Immunol. 2010;40(3):888–98.
  82. Reijerkerk A, et al. MicroRNAs regulate human brain endothelial cell-barrier function in inflammation: implications for multiple sclerosis. J Neurosci. 2013;33(16):6857–63.
  83. Haghikia A, et al, Regulated microRNAs in the CSF of patients with multiple sclerosis: a case-control study. Neurology. 2012;79(22):2166–70.
  84. Ebert PJ, et al. An endogenous positively selecting peptide enhances mature T cell responses and becomes an autoantigen in the absence of microRNA miR-181a. Nat Immunol. 2009;10(11):1162–9.
  85. Li QJ, et al. miR-181a is an intrinsic modulator of T cell sensitivity and selection. Cell. 2007;129(1):147–61.
  86. Neilson JR, et al. Dynamic regulation of miRNA expression in ordered stages of cellular development. Genes Dev. 2007;21(5):578–89.
  87. Bergman P, et al. Next-generation sequencing identifies microRNAs that associate with pathogenic autoimmune neuroinflammation in rats. J Immunol. 2013;190(8):4066–75.
  88. Tominaga N, et al. Brain metastatic cancer cells release microRNA-181c-containing extracellular vesicles capable of destructing blood-brain barrier. Nat Commun. 2015;6:6716.
  89. Zhao M, et al. DNA methylation and mRNA and microRNA expression of SLE CD4+ T cells correlate with disease phenotype. J Autoimmun. 2014;54:127–36.
  90. Mele F, et al. ERK phosphorylation and miR-181a expression modulate activation of human memory T17 cells. Nat Commun. 2015;6:6431.
  91. Garzon R, et al. MicroRNA-29b induces global DNA hypomethylation and tumor suppressor gene reexpression in acute myeloid leukemia by targeting directly DNMT3A and 3B and indirectly DNMT1. Blood. 2009;113(25):6411–8.
  92. Morita S, et al. miR-29 represses the activities of DNA methyltransferases and DNA demethylases. Int J Mol Sci. 2013;14(7):14647–58.
  93. Song SJ, et al. MicroRNA-antagonism regulates breast cancer stemness and metastasis via TET-family-dependent chromatin remodeling. Cell. 2013;154(2):311–24.
  94. Song SJ, et al. The oncogenic microRNA miR-22 targets the TET2 tumor suppressor to promote hematopoietic stem cell self-renewal and transformation. Cell Stem Cell. 2013;13(1):87–101.
  95. Cheng J, et al. An extensive network of TET2-targeting MicroRNAs regulates malignant hematopoiesis. Cell Rep. 2013;5(2):471–81.
  96. Lopez-Serra P, Esteller M. DNA methylation-associated silencing of tumor-suppressor microRNAs in cancer. Oncogene. 2012;31(13):1609–22.
  97. Mittelbrunn M, et al. Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells. Nat Commun. 2011;2:282.
  98. Okoye IS, et al. MicroRNA-containing T-regulatory-cell-derived exosomes suppress pathogenic T helper 1 cells. Immunity. 2014;41(1):89–103.
  99. Alarcon CR, et al. N6-methyladenosine marks primary microRNAs for processing. Nature. 2015;519(7544):482–5.
  100. Lee M, Kim B, Kim VN. Emerging roles of RNA modification: m(6)A and U-tail. Cell. 2014;158(5):980–7.
  101. O’Sullivan D, Pearce EL. Targeting T cell metabolism for therapy. Trends Immunol. 2015;36(2):71–80.
  102. Lochner M, Berod L, Sparwasser T. Fatty acid metabolism in the regulation of T cell function. Trends Immunol. 2015;36(2):81–91.
  103. Berod L, et al. De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat Med. 2014;20(11):1327–33.
  104. Moen EL, et al. New themes in the biological functions of 5-methylcytosine and 5-hydroxymethylcytosine. Immunol Rev. 2015;263(1):36–49.
  105. Dominguez-Salas P, et al. Maternal nutrition at conception modulates DNA methylation of human metastable epialleles. Nat Commun. 2014;5:3746.
  106. Jirtle RL, Skinner MK. Environmental epigenomics and disease susceptibility. Nat Rev Genet. 2007;8(4):253–62.
  107. Monfort A, Wutz A. Breathing-in epigenetic change with vitamin C. EMBO Rep. 2013;14(4):337–46.
  108. Blaschke K, et al. Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. Nature. 2013;500(7461):222–6.
  109. Koch MW, Metz LM, Kovalchuk O. Epigenetics and miRNAs in the diagnosis and treatment of multiple sclerosis. Trends Mol Med. 2013;19(1):23–30.
  110. Christman JK. 5-Azacytidine and 5-aza-2'-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy. Oncogene. 2002;21(35):5483–95.