Critical Link Between Epigenetics and Transcription Factors in the Induction of Autoimmunity: a Comprehensive Review

Abstract

Autoimmune diseases occur when the immune system loses tolerance to self-antigens, inducing inflammation and tissue damage. The pathogenesis of autoimmune diseases has not been elucidated. A growing mountain of evidence suggests the involvement of genetic and epigenetic factors in the development of these disorders. Genetic mapping has identified several candidate variants in autoimmune conditions. However, autoimmune diseases cannot be explained by genetic susceptibility alone. The fact that there is only 20 % of concordance for systemic lupus erythematosus (SLE) in homozygotic twins is an indication that epigenetics and environment may also play significant roles. Epigenetics refer to inheritable and potentially reversible changes in DNA and chromatin that regulate gene expression without altering the DNA sequence. The primary mechanisms of epigenetic regulation include DNA methylation, histone modification, and non-coding RNA-mediated regulation. The regulation on gene expression by epigenetics is similar to that by transcription factors (TFs), and the normal execution of biological event is controlled by a combination of epigenetic modifications and TFs. These two mechanisms share similar regulatory logistics and cooperate in part by influencing activity of the binding sites of target genes. In addition, the promoters of TFs have been found themselves to be modified by epigenetic regulators and TFs can also induce epigenetic changes. There is a two-way street in which interplay between epigenetic regulation and TFs plays a role in the pathogenesis of SLE, rheumatoid arthritis, type 1 diabetes, systemic sclerosis, and multiple sclerosis. Understanding of pathogenesis of these autoimmune diseases will help define potential targets for therapeutic strategies.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. 1.

    Lu Q (2014) Unmet needs in autoimmunity and potential new tools. Clin Rev Allergy Immunol 47:111–8

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Wandstrat A, Wakeland E (2001) The genetics of complex autoimmune diseases: non-MHC susceptibility genes. Nat Immunol 2:802–9

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Rhodes B, Vyse TJ (2008) The genetics of SLE: an update in the light of genome-wide association studies. Rheumatology (Oxford) 47:1603–11

    CAS  Article  Google Scholar 

  4. 4.

    Alarcon-Riquelme ME (2007) Recent advances in the genetics of autoimmune diseases. Ann N Y Acad Sci 1110:1–9

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Floreani A, Leung PS, Gershwin ME (2015) Environmental basis of autoimmunity Clin Rev Allergy Immunol

  6. 6.

    Jeffries MA, Sawalha AH (2011) Epigenetics in systemic lupus erythematosus: leading the way for specific therapeutic agents. Int J Clin Rheumatol 6:423–39

    CAS  Article  Google Scholar 

  7. 7.

    Ballestar E (2010) Epigenetics lessons from twins: prospects for autoimmune disease. Clin Rev Allergy Immunol 39:30–41

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Brown CC, Wedderburn LR (2015) Genetics: mapping autoimmune disease epigenetics: what’s on the horizon? Nat Rev Rheumatol 11:131–2

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Jeffries MA, Sawalha AH (2015) Autoimmune disease in the epigenetic era: how has epigenetics changed our understanding of disease and how can we expect the field to evolve? Expert Rev Clin Immunol 11:45–58

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Quddus J, Johnson KJ, Gavalchin J, Amento EP, Chrisp CE, Yung RL et al (1993) 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 92:38–53

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Sanchez-Pernaute O, Ospelt C, Neidhart M, Gay S (2008) Epigenetic clues to rheumatoid arthritis. J Autoimmun 30:12–20

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Kragt J, van Amerongen B, Killestein J, Dijkstra C, Uitdehaag B, Polman C et al (2009) Higher levels of 25-hydroxyvitamin D are associated with a lower incidence of multiple sclerosis only in women. Mult Scler 15:9–15

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Oksenberg JR, Baranzini SE, Sawcer S, Hauser SL (2008) The genetics of multiple sclerosis: SNPs to pathways to pathogenesis. Nat Rev Genet 9:516–26

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Koch MW, Metz LM, Kovalchuk O (2013) Epigenetics and miRNAs in the diagnosis and treatment of multiple sclerosis. Trends Mol Med 19:23–30

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Kucukali CI, Kurtuncu M, Coban A, Cebi M, Tuzun E (2014) Epigenetics of multiple sclerosis: an updated review. Neuromolecular Med

  16. 16.

    Strickland FM, Li Y, Johnson K, Sun Z, Richardson BC (2015) CD4(+) T cells epigenetically modified by oxidative stress cause lupus-like autoimmunity in mice. J Autoimmun 62:75–80

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Bao Y, Cao X (2015) Epigenetic control of B cell development and B-cell-related immune disorders. Clin Rev Allergy Immunol

  18. 18.

    Renauer P, Coit P, Sawalha AH (2015) Epigenetics and vasculitis: a comprehensive review. Clin Rev Allergy Immunol

  19. 19.

    Saito Y, Saito H, Liang G, Friedman JM (2014) Epigenetic alterations and microRNA misexpression in cancer and autoimmune diseases: a critical review. Clin Rev Allergy Immunol 47:128–35

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Bernstein BE, Meissner A, Lander ES (2007) The mammalian epigenome. Cell 128:669–81

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Denis H, Ndlovu MN, Fuks F (2011) Regulation of mammalian DNA methyltransferases: a route to new mechanisms. EMBO Rep 12:647–56

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Abdel-Wahab O, Mullally A, Hedvat C, Garcia-Manero G, Patel J, Wadleigh M et al (2009) Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood 114:144–7

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

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

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Klose RJ, Bird AP (2006) Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci 31:89–97

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Fan S, Zhang X (2009) CpG island methylation pattern in different human tissues and its correlation with gene expression. Biochem Biophys Res Commun 383:421–5

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Perini G, Diolaiti D, Porro A, Della Valle G (2005) In vivo transcriptional regulation of N-Myc target genes is controlled by E-box methylation. Proc Natl Acad Sci U S A 102:12117–22

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Kim J, Kollhoff A, Bergmann A, Stubbs L (2003) Methylation-sensitive binding of transcription factor YY1 to an insulator sequence within the paternally expressed imprinted gene, Peg3. Hum Mol Genet 12:233–45

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Chatterjee R, Vinson C (1819) CpG methylation recruits sequence specific transcription factors essential for tissue specific gene expression. Biochim Biophys Acta 2012:763–70

    Google Scholar 

  29. 29.

    Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, Eisenman RN et al (1998) Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393:386–9

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Medvedeva YA, Khamis AM, Kulakovskiy IV, Ba-Alawi W, Bhuyan MS, Kawaji H et al (2014) Effects of cytosine methylation on transcription factor binding sites. BMC Genomics 15:119

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  31. 31.

    Ali I, Seker H (2010) A comparative study for characterisation and prediction of tissue-specific DNA methylation of CpG islands in chromosomes 6, 20 and 22. Conf Proc IEEE Eng Med Biol Soc 2010:1832–5

    PubMed  Google Scholar 

  32. 32.

    Ghosh S, Yates AJ, Fruhwald MC, Miecznikowski JC, Plass C, Smiraglia D (2010) Tissue specific DNA methylation of CpG islands in normal human adult somatic tissues distinguishes neural from non-neural tissues. Epigenetics 5:527–38

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Cohen CJ, Crome SQ, MacDonald KG, Dai EL, Mager DL, Levings MK (2011) Human Th1 and Th17 cells exhibit epigenetic stability at signature cytokine and transcription factor loci. J Immunol 187:5615–26

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Ivascu C, Wasserkort R, Lesche R, Dong J, Stein H, Thiel A et al (2007) DNA methylation profiling of transcription factor genes in normal lymphocyte development and lymphomas. Int J Biochem Cell Biol 39:1523–38

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Perera A, Eisen D, Wagner M, Laube SK, Kunzel AF, Koch S et al (2015) TET3 is recruited by REST for context-specific hydroxymethylation and induction of gene expression. Cell Rep

  36. 36.

    Hervouet E, Vallette FM, Cartron PF (2010) Dnmt1/transcription factor interactions: an alternative mechanism of DNA methylation inheritance. Genes Cancer 1:434–43

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Zhang Q, Wang HY, Woetmann A, Raghunath PN, Odum N, Wasik MA (2006) STAT3 induces transcription of the DNA methyltransferase 1 gene (DNMT1) in malignant T lymphocytes. Blood 108:1058–64

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Rothbart SB, Strahl BD (1839) Interpreting the language of histone and DNA modifications. Biochim Biophys Acta 2014:627–43

    Google Scholar 

  39. 39.

    Peserico A, Simone C (2011) Physical and functional HAT/HDAC interplay regulates protein acetylation balance. J Biomed Biotechnol 2011:371832

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  40. 40.

    Renaudineau Y, Youinou P (2011) Epigenetics and autoimmunity, with special emphasis on methylation. Keio J Med 60:10–6

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Black JC, Van Rechem C, Whetstine JR (2012) Histone lysine methylation dynamics: establishment, regulation, and biological impact. Mol Cell 48:491–507

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Gregory PD, Wagner K, Horz W (2001) Histone acetylation and chromatin remodeling. Exp Cell Res 265:195–202

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Chuang HC, Chang CW, Chang GD, Yao TP, Chen H (2006) Histone deacetylase 3 binds to and regulates the GCMa transcription factor. Nucleic Acids Res 34:1459–69

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Yao YL, Yang WM, Seto E (2001) Regulation of transcription factor YY1 by acetylation and deacetylation. Mol Cell Biol 21:5979–91

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Katto J, Engel N, Abbas W, Herbein G, Mahlknecht U (2013) Transcription factor NFkappaB regulates the expression of the histone deacetylase SIRT1. Clin Epigenetics 5:11

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    Chen CZ, Li L, Lodish HF, Bartel DP (2004) MicroRNAs modulate hematopoietic lineage differentiation. Science 303:83–6

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Fabian MR, Sonenberg N, Filipowicz W (2010) Regulation of mRNA translation and stability by microRNAs. Annu Rev Biochem 79:351–79

    CAS  PubMed  Article  Google Scholar 

  48. 48.

    Inui M, Martello G, Piccolo S (2010) MicroRNA control of signal transduction. Nat Rev Mol Cell Biol 11:252–63

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136:215–33

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Baltimore D, Boldin MP, O’Connell RM, Rao DS, Taganov KD (2008) MicroRNAs: new regulators of immune cell development and function. Nat Immunol 9:839–45

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    O’Connell RM, Rao DS, Chaudhuri AA, Baltimore D (2010) Physiological and pathological roles for microRNAs in the immune system. Nat Rev Immunol 10:111–22

    PubMed  Article  CAS  Google Scholar 

  52. 52.

    Yan S, Yim LY, Lu L, Lau CS, Chan VS (2014) MicroRNA regulation in systemic lupus erythematosus pathogenesis. Immune Netw 14:138–48

    PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Johnson SM, Lin SY, Slack FJ (2003) The time of appearance of the C. elegans let-7 microRNA is transcriptionally controlled utilizing a temporal regulatory element in its promoter. Dev Biol 259:364–79

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    Biemar F, Zinzen R, Ronshaugen M, Sementchenko V, Manak JR, Levine MS (2005) Spatial regulation of microRNA gene expression in the Drosophila embryo. Proc Natl Acad Sci U S A 102:15907–11

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    Olson EN (2006) Gene regulatory networks in the evolution and development of the heart. Science 313:1922–7

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. 56.

    Arora S, Rana R, Chhabra A, Jaiswal A, Rani V (2013) miRNA-transcription factor interactions: a combinatorial regulation of gene expression. Mol Genet Genomics 288:77–87

    CAS  PubMed  Article  Google Scholar 

  57. 57.

    Chen CY, Chen ST, Fuh CS, Juan HF, Huang HC (2011) Coregulation of transcription factors and microRNAs in human transcriptional regulatory network. BMC Bioinformatics 12(Suppl 1):S41

    PubMed  PubMed Central  Article  Google Scholar 

  58. 58.

    Krol J, Loedige I, Filipowicz W (2010) The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet 11:597–610

    CAS  PubMed  Google Scholar 

  59. 59.

    Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A et al (2012) Landscape of transcription in human cells. Nature 489:101–8

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    International Human Genome Sequencing C (2004) Finishing the euchromatic sequence of the human genome. Nature 431:931–45

    Article  CAS  Google Scholar 

  61. 61.

    Rinn JL, Chang HY (2012) Genome regulation by long noncoding RNAs. Annu Rev Biochem 81:145–66

    CAS  PubMed  Article  Google Scholar 

  62. 62.

    Kretz M, Siprashvili Z, Chu C, Webster DE, Zehnder A, Qu K et al (2013) Control of somatic tissue differentiation by the long non-coding RNA TINCR. Nature 493:231–5

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. 63.

    Johnsson P, Ackley A, Vidarsdottir L, Lui WO, Corcoran M, Grander D et al (2013) A pseudogene long-noncoding-RNA network regulates PTEN transcription and translation in human cells. Nat Struct Mol Biol 20:440–6

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. 64.

    Wapinski O, Chang HY (2011) Long noncoding RNAs and human disease. Trends Cell Biol 21:354–61

    CAS  PubMed  Article  Google Scholar 

  65. 65.

    Li Z, Chao TC, Chang KY, Lin N, Patil VS, Shimizu C et al (2014) The long noncoding RNA THRIL regulates TNFalpha expression through its interaction with hnRNPL. Proc Natl Acad Sci U S A 111:1002–7

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. 66.

    Carpenter S, Aiello D, Atianand MK, Ricci EP, Gandhi P, Hall LL et al (2013) A long noncoding RNA mediates both activation and repression of immune response genes. Science 341:789–92

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. 67.

    Wang P, Xue Y, Han Y, Lin L, Wu C, Xu S et al (2014) The STAT3-binding long noncoding RNA lnc-DC controls human dendritic cell differentiation. Science 344:310–3

    CAS  PubMed  Article  Google Scholar 

  68. 68.

    Hu G, Tang Q, Sharma S, Yu F, Escobar TM, Muljo SA et al (2013) Expression and regulation of intergenic long noncoding RNAs during T cell development and differentiation. Nat Immunol 14:1190–8

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    Heward JA, Lindsay MA (2014) Long non-coding RNAs in the regulation of the immune response. Trends Immunol 35:408–19

    CAS  PubMed  Article  Google Scholar 

  70. 70.

    Hrdlickova B, Kumar V, Kanduri K, Zhernakova DV, Tripathi S, Karjalainen J et al (2014) Expression profiles of long non-coding RNAs located in autoimmune disease-associated regions reveal immune cell-type specificity. Genome Med 6:88

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  71. 71.

    Wang KC, Yang YW, Liu B, Sanyal A, Corces-Zimmerman R, Chen Y et al (2011) A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature 472:120–4

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72.

    Nagano T, Mitchell JA, Sanz LA, Pauler FM, Ferguson-Smith AC, Feil R et al (2008) The Air noncoding RNA epigenetically silences transcription by targeting G9a to chromatin. Science 322:1717–20

    CAS  PubMed  Article  Google Scholar 

  73. 73.

    Chen R, Yang Z, Zhou Q (2004) Phosphorylated positive transcription elongation factor b (P-TEFb) is tagged for inhibition through association with 7SK snRNA. J Biol Chem 279:4153–60

    CAS  PubMed  Article  Google Scholar 

  74. 74.

    Sharma S, Findlay GM, Bandukwala HS, Oberdoerffer S, Baust B, Li Z et al (2011) Dephosphorylation of the nuclear factor of activated T cells (NFAT) transcription factor is regulated by an RNA-protein scaffold complex. Proc Natl Acad Sci U S A 108:11381–6

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. 75.

    Beltran M, Puig I, Pena C, Garcia JM, Alvarez AB, Pena R et al (2008) A natural antisense transcript regulates Zeb2/Sip1 gene expression during Snail1-induced epithelial-mesenchymal transition. Genes Dev 22:756–69

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. 76.

    Annilo T, Kepp K, Laan M (2009) Natural antisense transcript of natriuretic peptide precursor A (NPPA): structural organization and modulation of NPPA expression. BMC Mol Biol 10:81

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  77. 77.

    D’Cruz DP, Khamashta MA, Hughes GR (2007) Systemic lupus erythematosus. Lancet 369:587–96

    PubMed  Article  Google Scholar 

  78. 78.

    Yu C, Gershwin ME, Chang C (2014) Diagnostic criteria for systemic lupus erythematosus: a critical review. J Autoimmun 48–49:10–3

    PubMed  Article  CAS  Google Scholar 

  79. 79.

    Tan EM, Kunkel HG (1966) Characteristics of a soluble nuclear antigen precipitating with sera of patients with systemic lupus erythematosus. J Immunol 96:464–71

    CAS  PubMed  Google Scholar 

  80. 80.

    Takeno M, Nagafuchi H, Kaneko S, Wakisaka S, Oneda K, Takeba Y et al (1997) Autoreactive T cell clones from patients with systemic lupus erythematosus support polyclonal autoantibody production. J Immunol 158:3529–38

    CAS  PubMed  Google Scholar 

  81. 81.

    Santulli-Marotto S, Retter MW, Gee R, Mamula MJ, Clarke SH (1998) Autoreactive B cell regulation: peripheral induction of developmental arrest by lupus-associated autoantigens. Immunity 8:209–19

    CAS  PubMed  Article  Google Scholar 

  82. 82.

    Gatto M, Zen M, Ghirardello A, Bettio S, Bassi N, Iaccarino L et al (2013) Emerging and critical issues in the pathogenesis of lupus. Autoimmun Rev 12:523–36

    CAS  PubMed  Article  Google Scholar 

  83. 83.

    Ghodke-Puranik Y, Niewold TB (2015) Immunogenetics of systemic lupus erythematosus: a comprehensive review. J Autoimmun 64:125–36

    CAS  PubMed  Article  Google Scholar 

  84. 84.

    Kuhn A, Wenzel J, Weyd H (2014) Photosensitivity, apoptosis, and cytokines in the pathogenesis of lupus erythematosus: a critical review. Clin Rev Allergy Immunol 47:148–62

    CAS  PubMed  Article  Google Scholar 

  85. 85.

    Meroni PL, Penatti AE (2015) Epigenetics and systemic lupus erythematosus: unmet needs. Clin Rev Allergy Immunol

  86. 86.

    Cannat A, Seligmann M (1968) Induction by isoniazid and hydrallazine of antinuclear factors in mice. Clin Exp Immunol 3:99–105

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Javierre BM, Fernandez AF, Richter J, Al-Shahrour F, Martin-Subero JI, Rodriguez-Ubreva J et al (2010) Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus. Genome Res 20:170–9

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. 88.

    Zhao M, Liu S, Luo S, Wu H, Tang M, Cheng W et al (2014) DNA methylation and mRNA and microRNA expression of SLE CD4+ T cells correlate with disease phenotype. J Autoimmun 54:127–36

    CAS  PubMed  Article  Google Scholar 

  89. 89.

    Zhou Y, Qiu X, Luo Y, Yuan J, Li Y, Zhong Q et al (2011) Histone modifications and methyl-CpG-binding domain protein levels at the TNFSF7 (CD70) promoter in SLE CD4+ T cells. Lupus 20:1365–71

    CAS  PubMed  Article  Google Scholar 

  90. 90.

    Zhao S, Wang Y, Liang Y, Zhao M, Long H, Ding S et al (2011) MicroRNA-126 regulates DNA methylation in CD4+ T cells and contributes to systemic lupus erythematosus by targeting DNA methyltransferase 1. Arthritis Rheum 63:1376–86

    CAS  PubMed  Article  Google Scholar 

  91. 91.

    Pan W, Zhu S, Yuan M, Cui H, Wang L, Luo X et al (2010) MicroRNA-21 and microRNA-148a contribute to DNA hypomethylation in lupus CD4+ T cells by directly and indirectly targeting DNA methyltransferase 1. J Immunol 184:6773–81

    CAS  PubMed  Article  Google Scholar 

  92. 92.

    Shi L, Zhang Z, Yu AM, Wang W, Wei Z, Akhter E et al (2014) The SLE transcriptome exhibits evidence of chronic endotoxin exposure and has widespread dysregulation of non-coding and coding RNAs. PLoS One 9, e93846

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  93. 93.

    Zhao M, Sun Y, Gao F, Wu X, Tang J, Yin H et al (2010) Epigenetics and SLE: RFX1 downregulation causes CD11a and CD70 overexpression by altering epigenetic modifications in lupus CD4+ T cells. J Autoimmun 35:58–69

    PubMed  Article  CAS  Google Scholar 

  94. 94.

    Zhao M, Wu X, Zhang Q, Luo S, Liang G, Su Y et al (2010) RFX1 regulates CD70 and CD11a expression in lupus T cells by recruiting the histone methyltransferase SUV39H1. Arthritis Res Ther 12:R227

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  95. 95.

    Zhao M, Liu Q, Liang G, Wang L, Luo S, Tang Q et al (2013) E4BP4 overexpression: a protective mechanism in CD4+ T cells from SLE patients. J Autoimmun 41:152–60

    CAS  PubMed  Article  Google Scholar 

  96. 96.

    Hedrich CM, Crispin JC, Rauen T, Ioannidis C, Apostolidis SA, Lo MS et al (2012) cAMP response element modulator alpha controls IL2 and IL17A expression during CD4 lineage commitment and subset distribution in lupus. Proc Natl Acad Sci U S A 109:16606–11

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. 97.

    Luo S, Liu Y, Liang G, Zhao M, Wu H, Liang Y et al (2015) The role of microRNA-1246 in the regulation of B cell activation and the pathogenesis of systemic lupus erythematosus. Clin Epigenetics 7:24

    PubMed  PubMed Central  Article  Google Scholar 

  98. 98.

    Kourilovitch M, Galarza-Maldonado C, Ortiz-Prado E (2014) Diagnosis and classification of rheumatoid arthritis. J Autoimmun 48–49:26–30

    PubMed  Article  CAS  Google Scholar 

  99. 99.

    Zhu X, Song Y, Huo R, Zhang J, Sun S, He Y et al (2015) Cyr61 participates in the pathogenesis of rheumatoid arthritis by promoting proIL-1beta production by fibroblast-like synoviocytes through an AKT-dependent NF-kappaB signaling pathway. Clin Immunol 157:187–97

    CAS  PubMed  Article  Google Scholar 

  100. 100.

    Klein K, Gay S (2015) Epigenetics in rheumatoid arthritis. Curr Opin Rheumatol 27:76–82

    CAS  PubMed  Article  Google Scholar 

  101. 101.

    Kuchen S, Seemayer CA, Rethage J, von Knoch R, Kuenzler P, Beat AM et al (2004) The L1 retroelement-related p40 protein induces p38delta MAP kinase. Autoimmunity 37:57–65

    CAS  PubMed  Article  Google Scholar 

  102. 102.

    Grabiec AM, Tak PP, Reedquist KA (2008) Targeting histone deacetylase activity in rheumatoid arthritis and asthma as prototypes of inflammatory disease: should we keep our HATs on? Arthritis Res Ther 10:226

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  103. 103.

    Nakamachi Y, Kawano S, Takenokuchi M, Nishimura K, Sakai Y, Chin T et al (2009) MicroRNA-124a is a key regulator of proliferation and monocyte chemoattractant protein 1 secretion in fibroblast-like synoviocytes from patients with rheumatoid arthritis. Arthritis Rheum 60:1294–304

    PubMed  Article  Google Scholar 

  104. 104.

    Muller N, Doring F, Klapper M, Neumann K, Schulte DM, Turk K et al (2014) Interleukin-6 and tumour necrosis factor-alpha differentially regulate lincRNA transcripts in cells of the innate immune system in vivo in human subjects with rheumatoid arthritis. Cytokine 68:65–8

    CAS  PubMed  Article  Google Scholar 

  105. 105.

    Kawahara TL, Michishita E, Adler AS, Damian M, Berber E, Lin M et al (2009) SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span. Cell 136:62–74

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  106. 106.

    Takami N, Osawa K, Miura Y, Komai K, Taniguchi M, Shiraishi M et al (2006) Hypermethylated promoter region of DR3, the death receptor 3 gene, in rheumatoid arthritis synovial cells. Arthritis Rheum 54:779–87

    CAS  PubMed  Article  Google Scholar 

  107. 107.

    Bull MJ, Williams AS, Mecklenburgh Z, Calder CJ, Twohig JP, Elford C et al (2008) The Death Receptor 3-TNF-like protein 1A pathway drives adverse bone pathology in inflammatory arthritis. J Exp Med 205:2457–64

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  108. 108.

    Suarez-Alvarez B, Rodriguez RM, Fraga MF, Lopez-Larrea C (2012) DNA methylation: a promising landscape for immune system-related diseases. Trends Genet 28:506–14

    CAS  PubMed  Article  Google Scholar 

  109. 109.

    Kosmaczewska A, Ciszak L, Swierkot J, Szteblich A, Kosciow K, Frydecka I (2015) Exogenous IL-2 controls the balance in Th1, Th17, and Treg cell distribution in patients with progressive rheumatoid arthritis treated with TNF-alpha inhibitors. Inflammation 38:765–74

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  110. 110.

    Xie Z, Chang C, Zhou Z (2014) Molecular mechanisms in autoimmune type 1 diabetes: a critical review. Clin Rev Allergy Immunol 47:174–92

    CAS  PubMed  Article  Google Scholar 

  111. 111.

    Burgio E, Lopomo A, Migliore L (2015) Obesity and diabetes: from genetics to epigenetics. Mol Biol Rep 42:799–818

    CAS  PubMed  Article  Google Scholar 

  112. 112.

    Noble JA (2015) Immunogenetics of type 1 diabetes: a comprehensive review. J Autoimmun 64:101–12

    CAS  PubMed  Article  Google Scholar 

  113. 113.

    Dang MN, Buzzetti R, Pozzilli P (2013) Epigenetics in autoimmune diseases with focus on type 1 diabetes. Diabetes Metab Res Rev 29:8–18

    CAS  PubMed  Article  Google Scholar 

  114. 114.

    Stefan M, Zhang W, Concepcion E, Yi Z, Tomer Y (2014) DNA methylation profiles in type 1 diabetes twins point to strong epigenetic effects on etiology. J Autoimmun 50:33–7

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. 115.

    Miao F, Smith DD, Zhang L, Min A, Feng W, Natarajan R (2008) Lymphocytes from patients with type 1 diabetes display a distinct profile of chromatin histone H3 lysine 9 dimethylation: an epigenetic study in diabetes. Diabetes 57:3189–98

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  116. 116.

    Elboudwarej E, Cole M, Briggs FB, Fouts A, Fain PR, Quach H et al (2016) Hypomethylation within gene promoter regions and type 1 diabetes in discordant monozygotic twins. Journal of autoimmunity

  117. 117.

    Li Y, Reddy MA, Miao F, Shanmugam N, Yee JK, Hawkins D et al (2008) Role of the histone H3 lysine 4 methyltransferase, SET7/9, in the regulation of NF-kappaB-dependent inflammatory genes. Relevance to diabetes and inflammation. J Biol Chem 283:26771–81

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  118. 118.

    Brasacchio D, Okabe J, Tikellis C, Balcerczyk A, George P, Baker EK et al (2009) Hyperglycemia induces a dynamic cooperativity of histone methylase and demethylase enzymes associated with gene-activating epigenetic marks that coexist on the lysine tail. Diabetes 58:1229–36

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. 119.

    Wang Z, Zheng Y, Hou C, Yang L, Li X, Lin J et al (2013) DNA methylation impairs TLR9 induced Foxp3 expression by attenuating IRF-7 binding activity in fulminant type 1 diabetes. J Autoimmun 41:50–9

    PubMed  Article  CAS  Google Scholar 

  120. 120.

    Tan T, Xiang Y, Chang C, Zhou Z (2014) Alteration of regulatory T cells in type 1 diabetes mellitus: a comprehensive review. Clin Rev Allergy Immunol 47:234–43

    CAS  PubMed  Article  Google Scholar 

  121. 121.

    Bettini ML, Pan F, Bettini M, Finkelstein D, Rehg JE, Floess S et al (2012) Loss of epigenetic modification driven by the Foxp3 transcription factor leads to regulatory T cell insufficiency. Immunity 36:717–30

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  122. 122.

    Hudson M, Fritzler MJ (2014) Diagnostic criteria of systemic sclerosis. J Autoimmun 48–49:38–41

    PubMed  Article  CAS  Google Scholar 

  123. 123.

    Ciechomska M, van Laar JM, O’Reilly S (2014) Emerging role of epigenetics in systemic sclerosis pathogenesis. Genes Immun 15:433–9

    CAS  PubMed  Article  Google Scholar 

  124. 124.

    Maurer B, Stanczyk J, Jungel A, Akhmetshina A, Trenkmann M, Brock M et al (2010) MicroRNA-29, a key regulator of collagen expression in systemic sclerosis. Arthritis Rheum 62:1733–43

    CAS  PubMed  Article  Google Scholar 

  125. 125.

    Lei W, Luo Y, Lei W, Luo Y, Yan K, Zhao S et al (2009) Abnormal DNA methylation in CD4+ T cells from patients with systemic lupus erythematosus, systemic sclerosis, and dermatomyositis. Scand J Rheumatol 38:369–74

    CAS  PubMed  Article  Google Scholar 

  126. 126.

    Lian X, Xiao R, Hu X, Kanekura T, Jiang H, Li Y et al (2012) DNA demethylation of CD40l in CD4+ T cells from women with systemic sclerosis: a possible explanation for female susceptibility. Arthritis Rheum 64:2338–45

    CAS  PubMed  Article  Google Scholar 

  127. 127.

    Wang YY, Wang Q, Sun XH, Liu RZ, Shu Y, Kanekura T et al (2014) DNA hypermethylation of the forkhead box protein 3 (FOXP3) promoter in CD4+ T cells of patients with systemic sclerosis. Br J Dermatol 171:39–47

    CAS  PubMed  Article  Google Scholar 

  128. 128.

    Wang Y, Shu Y, Xiao Y, Wang Q, Kanekura T, Li Y et al (2014) Hypomethylation and overexpression of ITGAL (CD11a) in CD4(+) T cells in systemic sclerosis. Clin Epigenetics 6:25

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  129. 129.

    Kubo M, Czuwara-Ladykowska J, Moussa O, Markiewicz M, Smith E, Silver RM et al (2003) Persistent down-regulation of Fli1, a suppressor of collagen transcription, in fibrotic scleroderma skin. Am J Pathol 163:571–81

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  130. 130.

    Wang Y, Fan PS, Kahaleh B (2006) Association between enhanced type I collagen expression and epigenetic repression of the FLI1 gene in scleroderma fibroblasts. Arthritis Rheum 54:2271–9

    CAS  PubMed  Article  Google Scholar 

  131. 131.

    Broen JC, Coenen MJ, Radstake TR (2011) Deciphering the genetic background of systemic sclerosis. Expert Rev Clin Immunol 7:449–62

    CAS  PubMed  Article  Google Scholar 

  132. 132.

    Huber LC, Distler JH, Moritz F, Hemmatazad H, Hauser T, Michel BA et al (2007) Trichostatin A prevents the accumulation of extracellular matrix in a mouse model of bleomycin-induced skin fibrosis. Arthritis Rheum 56:2755–64

    CAS  PubMed  Article  Google Scholar 

  133. 133.

    Hollenbach JA, Oksenberg JR (2015) The immunogenetics of multiple sclerosis: a comprehensive review. J Autoimmun 64:13–25

    CAS  PubMed  Article  Google Scholar 

  134. 134.

    Yang H, Lee SM, Gao B, Zhang J, Fang D (2013) Histone deacetylase sirtuin 1 deacetylates IRF1 protein and programs dendritic cells to control Th17 protein differentiation during autoimmune inflammation. J Biol Chem 288:37256–66

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  135. 135.

    Liu B, Tahk S, Yee KM, Fan G, Shuai K (2010) The ligase PIAS1 restricts natural regulatory T cell differentiation by epigenetic repression. Science 330:521–5

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  136. 136.

    Guan H, Nagarkatti PS, Nagarkatti M (2011) CD44 Reciprocally regulates the differentiation of encephalitogenic Th1/Th17 and Th2/regulatory T cells through epigenetic modulation involving DNA methylation of cytokine gene promoters, thereby controlling the development of experimental autoimmune encephalomyelitis. J Immunol 186:6955–64

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  137. 137.

    Lu LF, Thai TH, Calado DP, Chaudhry A, Kubo M, Tanaka K et al (2009) Foxp3-dependent microRNA155 confers competitive fitness to regulatory T cells by targeting SOCS1 protein. Immunity 30:80–91

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (grant no. 81220108017, no. 81430074, no. 81373205, and no. 81270024), the Specialized Research Fund for the Doctoral Program of Higher Education (grant no. 20120162130003), and Hunan Natural Science Funds for Distinguished Young Scientists (No. 14JJ1009).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Qianjin Lu.

Additional information

Haijing Wu and Ming Zhao contributed equally to this work.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wu, H., Zhao, M., Yoshimura, A. et al. Critical Link Between Epigenetics and Transcription Factors in the Induction of Autoimmunity: a Comprehensive Review. Clinic Rev Allerg Immunol 50, 333–344 (2016). https://doi.org/10.1007/s12016-016-8534-y

Download citation

Keywords

  • Epigenetics
  • Transcription factors
  • DNA methylation
  • Histone modifications
  • miRNAs
  • lncRNAs
  • Autoimmune