Clinical Reviews in Allergy & Immunology

, Volume 39, Issue 1, pp 10–19 | Cite as

Epigenetics in Rheumatoid Arthritis

  • Michelle Trenkmann
  • Matthias Brock
  • Caroline Ospelt
  • Steffen GayEmail author


Epigenetics is a steadily growing research area. In many human diseases, especially in cancers, but also in autoimmune diseases, epigenetic aberrations have been found. Rheumatoid arthritis is an autoimmune disease characterized by chronic inflammation and destruction of synovial joints. Even though the etiology is not yet fully understood, rheumatoid arthritis is generally considered to be caused by a combination of genetic predisposition, deregulated immunomodulation, and environmental influences. To gain a better understanding of this disease, researchers have become interested in studying epigenetic changes in rheumatoid arthritis. Here, we want to review the current knowledge on epigenetics in rheumatoid arthritis.


Rheumatoid arthritis Histone Histone deacetylases 


  1. 1.
    Firestein GS (2003) Evolving concepts of rheumatoid arthritis. Nature 423:356–361PubMedCrossRefGoogle Scholar
  2. 2.
    Lipsky PE (2007) Why does rheumatoid arthritis involve the joints? N Engl J Med 356:2419–2420PubMedCrossRefGoogle Scholar
  3. 3.
    Ospelt C, Gay S (2008) The role of resident synovial cells in destructive arthritis. Best Pract Res Clin Rheumatol 22:239–252PubMedCrossRefGoogle Scholar
  4. 4.
    Smith JB, Haynes MK (2002) Rheumatoid arthritis—a molecular understanding. Ann Intern Med 136:908–922PubMedGoogle Scholar
  5. 5.
    Ermann J, Fathman CG (2001) Autoimmune diseases: genes, bugs and failed regulation. Nat Immunol 2:759–761PubMedCrossRefGoogle Scholar
  6. 6.
    Bird A (2007) Perceptions of epigenetics. Nature 447:396–398PubMedCrossRefGoogle Scholar
  7. 7.
    Hirst M, Marra MA (2009) Epigenetics and human disease. Int J Biochem Cell Biol 41:136–146PubMedCrossRefGoogle Scholar
  8. 8.
    Feinberg AP (2007) Phenotypic plasticity and the epigenetics of human disease. Nature 447:433–440PubMedCrossRefGoogle Scholar
  9. 9.
    Kouzarides T (2007) Chromatin modifications and their function. Cell 128:693–705PubMedCrossRefGoogle Scholar
  10. 10.
    Berger SL (2007) The complex language of chromatin regulation during transcription. Nature 447:407–412PubMedCrossRefGoogle Scholar
  11. 11.
    Lee GR, Kim ST, Spilianakis CG, Fields PE, Flavell RA (2006) T helper cell differentiation: regulation by cis elements and epigenetics. Immunity 24:369–379PubMedCrossRefGoogle Scholar
  12. 12.
    Su IH, Tarakhovsky A (2005) Epigenetic control of B cell differentiation. Semin Immunol 17:167–172PubMedCrossRefGoogle Scholar
  13. 13.
    De Santa F, Totaro MG, Prosperini E, Notarbartolo S, Testa G, Natoli G (2007) The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing. Cell 130:1083–1094PubMedCrossRefGoogle Scholar
  14. 14.
    Bhaumik SR, Smith E, Shilatifard A (2007) Covalent modifications of histones during development and disease pathogenesis. Nat Struct Mol Biol 14:1008–1016PubMedCrossRefGoogle Scholar
  15. 15.
    Strahl BD, Allis CD (2000) The language of covalent histone modifications. Nature 403:41–45PubMedCrossRefGoogle Scholar
  16. 16.
    Haberland M, Montgomery RL, Olson EN (2009) The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet 10:32–42PubMedCrossRefGoogle Scholar
  17. 17.
    Roth SY, Denu JM, Allis CD (2001) Histone acetyltransferases. Annu Rev Biochem 70:81–120PubMedCrossRefGoogle Scholar
  18. 18.
    Smith BC, Denu JM (2009) Chemical mechanisms of histone lysine and arginine modifications. Biochim Biophys Acta 1789:45–57PubMedGoogle Scholar
  19. 19.
    Chang B, Chen Y, Zhao Y, Bruick RK (2007) JMJD6 is a histone arginine demethylase. Science 318:444–447PubMedCrossRefGoogle Scholar
  20. 20.
    Wang Y, Wysocka J, Sayegh J et al (2004) Human PAD4 regulates histone arginine methylation levels via demethylimination. Science 306:279–283PubMedCrossRefGoogle Scholar
  21. 21.
    Sadoul K, Boyault C, Pabion M, Khochbin S (2008) Regulation of protein turnover by acetyltransferases and deacetylases. Biochimie 90:306–312PubMedCrossRefGoogle Scholar
  22. 22.
    Huang J, Berger SL (2008) The emerging field of dynamic lysine methylation of non-histone proteins. Curr Opin Genet Dev 18:152–158PubMedCrossRefGoogle Scholar
  23. 23.
    Avni O, Lee D, Macian F, Szabo SJ, Glimcher LH, Rao A (2002) T(H) cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes. Nat Immunol 3:643–651PubMedCrossRefGoogle Scholar
  24. 24.
    Baguet A, Bix M (2004) Chromatin landscape dynamics of the Il4-Il13 locus during T helper 1 and 2 development. Proc Natl Acad Sci U S A 101:11410–11415PubMedCrossRefGoogle Scholar
  25. 25.
    Koyanagi M, Baguet A, Martens J, Margueron R, Jenuwein T, Bix M (2005) EZH2 and histone 3 trimethyl lysine 27 associated with Il4 and Il13 gene silencing in Th1 cells. J Biol Chem 280:31470–31477PubMedCrossRefGoogle Scholar
  26. 26.
    Chang S, Aune TM (2007) Dynamic changes in histone-methylation ‘marks’ across the locus encoding interferon-gamma during the differentiation of T helper type 2 cells. Nat Immunol 8:723–731PubMedCrossRefGoogle Scholar
  27. 27.
    Raza K, Falciani F, Curnow SJ et al (2005) Early rheumatoid arthritis is characterized by a distinct and transient synovial fluid cytokine profile of T cell and stromal cell origin. Arthritis Res Ther 7:R784–R795PubMedCrossRefGoogle Scholar
  28. 28.
    Vittecoq O, Lequerre T, Goeb V, Le Loet X, Abdesselam TA, Klemmer N (2008) Smoking and inflammatory diseases. Best Pract Res Clin Rheumatol 22:923–935PubMedCrossRefGoogle Scholar
  29. 29.
    Yang SR, Wright J, Bauter M, Seweryniak K, Kode A, Rahman I (2007) Sirtuin regulates cigarette smoke-induced proinflammatory mediator release via RelA/p65 NF-kappaB in macrophages in vitro and in rat lungs in vivo: implications for chronic inflammation and aging. Am J Physiol Lung Cell Mol Physiol 292:L567–L576PubMedCrossRefGoogle Scholar
  30. 30.
    Kawahara TL, Michishita E, Adler AS et al (2009) SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span. Cell 136:62–74PubMedCrossRefGoogle Scholar
  31. 31.
    Van Gool F, Galli M, Gueydan C et al (2009) Intracellular NAD levels regulate tumor necrosis factor protein synthesis in a sirtuin-dependent manner. Nat Med 15:206–210PubMedCrossRefGoogle Scholar
  32. 32.
    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 10:226PubMedCrossRefGoogle Scholar
  33. 33.
    Nishida K, Komiyama T, Miyazawa S et al (2004) Histone deacetylase inhibitor suppression of autoantibody-mediated arthritis in mice via regulation of p16INK4a and p21(WAF1/Cip1) expression. Arthritis Rheum 50:3365–3376PubMedCrossRefGoogle Scholar
  34. 34.
    Lin HS, Hu CY, Chan HY et al (2007) Anti-rheumatic activities of histone deacetylase (HDAC) inhibitors in vivo in collagen-induced arthritis in rodents. Br J Pharmacol 150:862–872PubMedCrossRefGoogle Scholar
  35. 35.
    Nakamura T, Kukita T, Shobuike T et al (2005) Inhibition of histone deacetylase suppresses osteoclastogenesis and bone destruction by inducing IFN-beta production. J Immunol 175:5809–5816PubMedGoogle Scholar
  36. 36.
    Schett G (2009) Osteoimmunology in rheumatic diseases. Arthritis Res Ther 11:210PubMedCrossRefGoogle Scholar
  37. 37.
    Nasu Y, Nishida K, Miyazawa S et al (2008) Trichostatin A, a histone deacetylase inhibitor, suppresses synovial inflammation and subsequent cartilage destruction in a collagen antibody-induced arthritis mouse model. Osteoarthritis Cartilage 16:723–732PubMedCrossRefGoogle Scholar
  38. 38.
    Huber LC, Brock M, Hemmatazad H et al (2007) Histone deacetylase/acetylase activity in total synovial tissue derived from rheumatoid arthritis and osteoarthritis patients. Arthritis Rheum 56:1087–1093PubMedCrossRefGoogle Scholar
  39. 39.
    Xu WS, Parmigiani RB, Marks PA (2007) Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene 26:5541–5552PubMedCrossRefGoogle Scholar
  40. 40.
    Nakashima K, Hagiwara T, Yamada M (2002) Nuclear localization of peptidylarginine deiminase V and histone deimination in granulocytes. J Biol Chem 277:49562–49568PubMedCrossRefGoogle Scholar
  41. 41.
    Zendman AJ, van Venrooij WJ, Pruijn GJ (2006) Use and significance of anti-CCP autoantibodies in rheumatoid arthritis. Rheumatology (Oxford) 45:20–25CrossRefGoogle Scholar
  42. 42.
    Chang X, Yamada R, Suzuki A et al (2005) Localization of peptidylarginine deiminase 4 (PADI4) and citrullinated protein in synovial tissue of rheumatoid arthritis. Rheumatology (Oxford) 44:40–50CrossRefGoogle Scholar
  43. 43.
    Vossenaar ER, Radstake TR, van der Heijden A et al (2004) Expression and activity of citrullinating peptidylarginine deiminase enzymes in monocytes and macrophages. Ann Rheum Dis 63:373–381PubMedCrossRefGoogle Scholar
  44. 44.
    Chang X, Zhao Y, Sun S, Zhang Y, Zhu Y (2009) The expression of PADI4 in synovium of rheumatoid arthritis. Rheumatol Int . doi: 10.1007/s00296-009-0870-2 Google Scholar
  45. 45.
    Wang Y, Li M, Stadler S et al (2009) Histone hypercitrullination mediates chromatin decondensation and neutrophil extracellular trap formation. J Cell Biol 184:205–213PubMedCrossRefGoogle Scholar
  46. 46.
    Neeli I, Khan SN, Radic M (2008) Histone deimination as a response to inflammatory stimuli in neutrophils. J Immunol 180:1895–1902PubMedGoogle Scholar
  47. 47.
    Klose RJ, Bird AP (2006) Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci 31:89–97PubMedCrossRefGoogle Scholar
  48. 48.
    Chiang PK, Gordon RK, Tal J et al (1996) S-Adenosylmethionine and methylation. FASEB J 10:471–480PubMedGoogle Scholar
  49. 49.
    Bird AP, Wolffe AP (1999) Methylation-induced repression—belts, braces, and chromatin. Cell 99:451–454PubMedCrossRefGoogle Scholar
  50. 50.
    Bruniquel D, Schwartz RH (2003) Selective, stable demethylation of the interleukin-2 gene enhances transcription by an active process. Nat Immunol 4:235–240PubMedCrossRefGoogle Scholar
  51. 51.
    Sullivan KE, Reddy AB, Dietzmann K et al (2007) Epigenetic regulation of tumor necrosis factor alpha. Mol Cell Biol 27:5147–5160PubMedCrossRefGoogle Scholar
  52. 52.
    McInnes IB, Schett G (2007) Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol 7:429–442PubMedCrossRefGoogle Scholar
  53. 53.
    Richardson B, Scheinbart L, Strahler J, Gross L, Hanash S, Johnson M (1990) Evidence for impaired T cell DNA methylation in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum 33:1665–1673PubMedCrossRefGoogle Scholar
  54. 54.
    Neidhart M, Rethage J, Kuchen S et al (2000) Retrotransposable L1 elements expressed in rheumatoid arthritis synovial tissue: association with genomic DNA hypomethylation and influence on gene expression. Arthritis Rheum 43:2634–2647PubMedCrossRefGoogle Scholar
  55. 55.
    Nile CJ, Read RC, Akil M, Duff GW, Wilson AG (2008) Methylation status of a single CpG site in the IL6 promoter is related to IL6 messenger RNA levels and rheumatoid arthritis. Arthritis Rheum 58:2686–2693PubMedCrossRefGoogle Scholar
  56. 56.
    Das PM, Singal R (2004) DNA methylation and cancer. J Clin Oncol 22:4632–4642PubMedCrossRefGoogle Scholar
  57. 57.
    Otterson GA, Khleif SN, Chen W, Coxon AB, Kaye FJ (1995) CDKN2 gene silencing in lung cancer by DNA hypermethylation and kinetics of p16INK4 protein induction by 5-aza 2′deoxycytidine. Oncogene 11:1211–1216PubMedGoogle Scholar
  58. 58.
    Katzenellenbogen RA, Baylin SB, Herman JG (1999) Hypermethylation of the DAP-kinase CpG island is a common alteration in B-cell malignancies. Blood 93:4347–4353PubMedGoogle Scholar
  59. 59.
    Dobrovic A, Simpfendorfer D (1997) Methylation of the BRCA1 gene in sporadic breast cancer. Cancer Res 57:3347–3350PubMedGoogle Scholar
  60. 60.
    Kang SH, Choi HH, Kim SG et al (2000) Transcriptional inactivation of the tissue inhibitor of metalloproteinase-3 gene by dna hypermethylation of the 5′-CpG island in human gastric cancer cell lines. Int J Cancer 86:632–635PubMedCrossRefGoogle Scholar
  61. 61.
    Takami N, Osawa K, Miura Y et al (2006) Hypermethylated promoter region of DR3, the death receptor 3 gene, in rheumatoid arthritis synovial cells. Arthritis Rheum 54:779–787PubMedCrossRefGoogle Scholar
  62. 62.
    Ashkenazi A, Dixit VM (1998) Death receptors: signaling and modulation. Science 281:1305–1308PubMedCrossRefGoogle Scholar
  63. 63.
    Wang GG, Allis CD, Chi P (2007) Chromatin remodeling and cancer. Part II: ATP-dependent chromatin remodeling. Trends Mol Med 13:373–380PubMedCrossRefGoogle Scholar
  64. 64.
    Costa FF (2008) Non-coding RNAs, epigenetics and complexity. Gene 410:9–17PubMedCrossRefGoogle Scholar
  65. 65.
    Ng K, Pullirsch D, Leeb M, Wutz A (2007) Xist and the order of silencing. EMBO Rep 8:34–39PubMedCrossRefGoogle Scholar
  66. 66.
    Wutz A (2007) Xist function: bridging chromatin and stem cells. Trends Genet 23:457–464PubMedCrossRefGoogle Scholar
  67. 67.
    Wutz A, Gribnau J (2007) X inactivation Xplained. Curr Opin Genet Dev 17:387–393PubMedCrossRefGoogle Scholar
  68. 68.
    Ozcelik T (2008) X chromosome inactivation and female predisposition to autoimmunity. Clin Rev Allergy Immunol 34:348–351PubMedCrossRefGoogle Scholar
  69. 69.
    Lu Q, Wu A, Tesmer L, Ray D, Yousif N, Richardson B (2007) Demethylation of CD40LG on the inactive X in T cells from women with lupus. J Immunol 179:6352–6358PubMedGoogle Scholar
  70. 70.
    Uz E, Loubiere LS, Gadi VK et al (2008) Skewed X-chromosome inactivation in scleroderma. Clin Rev Allergy Immunol 34:352–355PubMedCrossRefGoogle Scholar
  71. 71.
    Bernstein E, Allis CD (2005) RNA meets chromatin. Genes Dev 19:1635–1655PubMedCrossRefGoogle Scholar
  72. 72.
    Moazed D (2009) Small RNAs in transcriptional gene silencing and genome defence. Nature 457:413–420PubMedCrossRefGoogle Scholar
  73. 73.
    Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75:843–854PubMedCrossRefGoogle Scholar
  74. 74.
    Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297PubMedCrossRefGoogle Scholar
  75. 75.
    Faller M, Guo F (2008) MicroRNA biogenesis: there's more than one way to skin a cat. Biochim Biophys Acta 1779:663–667PubMedGoogle Scholar
  76. 76.
    Mendell JT (2005) MicroRNAs: critical regulators of development, cellular physiology and malignancy. Cell Cycle 4:1179–1184PubMedGoogle Scholar
  77. 77.
    Zeng Y, Yi R, Cullen BR (2003) MicroRNAs and small interfering RNAs can inhibit mRNA expression by similar mechanisms. Proc Natl Acad Sci U S A 100:9779–9784PubMedCrossRefGoogle Scholar
  78. 78.
    Lewis BP, Burge CB, Bartel DP (2005) Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120:15–20PubMedCrossRefGoogle Scholar
  79. 79.
    Cloonan N, Brown MK, Steptoe AL et al (2008) The miR-17–5p microRNA is a key regulator of the G1/S phase cell cycle transition. Genome Biol 9:R127PubMedCrossRefGoogle Scholar
  80. 80.
    Cimmino A, Calin GA, Fabbri M et al (2005) miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci U S A 102:13944–13949PubMedCrossRefGoogle Scholar
  81. 81.
    Kim HK, Lee YS, Sivaprasad U, Malhotra A, Dutta A (2006) Muscle-specific microRNA miR-206 promotes muscle differentiation. J Cell Biol 174:677–687PubMedCrossRefGoogle Scholar
  82. 82.
    O'Connell RM, Taganov KD, Boldin MP, Cheng G, Baltimore D (2007) MicroRNA-155 is induced during the macrophage inflammatory response. Proc Natl Acad Sci U S A 104:1604–1609PubMedCrossRefGoogle Scholar
  83. 83.
    Seibl R, Birchler T, Loeliger S et al (2003) Expression and regulation of Toll-like receptor 2 in rheumatoid arthritis synovium. Am J Pathol 162:1221–1227PubMedGoogle Scholar
  84. 84.
    Stanczyk J, Pedrioli DM, Brentano F et al (2008) Altered expression of MicroRNA in synovial fibroblasts and synovial tissue in rheumatoid arthritis. Arthritis Rheum 58:1001–1009PubMedCrossRefGoogle Scholar
  85. 85.
    Ceppi M, Pereira PM, Dunand-Sauthier I et al (2009) MicroRNA-155 modulates the interleukin-1 signaling pathway in activated human monocyte-derived dendritic cells. Proc Natl Acad Sci U S A 106:2735–2740PubMedCrossRefGoogle Scholar
  86. 86.
    Nakasa T, Miyaki S, Okubo A et al (2008) Expression of microRNA-146 in rheumatoid arthritis synovial tissue. Arthritis Rheum 58:1284–1292PubMedCrossRefGoogle Scholar
  87. 87.
    Pauley KM, Satoh M, Chan AL, Bubb MR, Reeves WH, Chan EK (2008) Upregulated miR-146a expression in peripheral blood mononuclear cells from rheumatoid arthritis patients. Arthritis Res Ther 10:R101PubMedCrossRefGoogle Scholar
  88. 88.
    Taganov KD, Boldin MP, Chang KJ, Baltimore D (2006) NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci U S A 103:12481–12486PubMedCrossRefGoogle Scholar
  89. 89.
    Selbach M, Schwanhausser B, Thierfelder N, Fang Z, Khanin R, Rajewsky N (2008) Widespread changes in protein synthesis induced by microRNAs. Nature 455:58–63PubMedCrossRefGoogle Scholar
  90. 90.
    Fraga MF, Ballestar E, Paz MF et al (2005) Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A 102:10604–10609PubMedCrossRefGoogle Scholar
  91. 91.
    Jarvinen P, Aho K (1994) Twin studies in rheumatic diseases. Semin Arthritis Rheum 24:19–28PubMedCrossRefGoogle Scholar
  92. 92.
    Arnheim N, Calabrese P (2009) Understanding what determines the frequency and pattern of human germline mutations. Nat Rev Genet 10:478–488PubMedCrossRefGoogle Scholar
  93. 93.
    Barros SP, Offenbacher S (2009) Epigenetics: connecting environment and genotype to phenotype and disease. J Dent Res 88:400–408PubMedCrossRefGoogle Scholar
  94. 94.
    Figueiredo LM, Cross GA, Janzen CJ (2009) Epigenetic regulation in African trypanosomes: a new kid on the block. Nat Rev Microbiol 7:504–513PubMedCrossRefGoogle Scholar
  95. 95.
    Hewagama A, Richardson B (2009) The genetics and epigenetics of autoimmune diseases. J Autoimmun 33:3–11PubMedCrossRefGoogle Scholar
  96. 96.
    Invernizzi P (2009) Future directions in genetic for autoimmune diseases. J Autoimmun 33:1–2PubMedCrossRefGoogle Scholar
  97. 97.
    Invernizzi P, Pasini S, Selmi C, Gershwin ME, Podda M (2009) Female predominance and X chromosome defects in autoimmune diseases. J Autoimmun 33:12–16PubMedCrossRefGoogle Scholar
  98. 98.
    Larizza D, Calcaterra V, Martinetti M (2009) Autoimmune stigmata in Turner syndrome: when lacks an X chromosome. J Autoimmun 33:25–30PubMedCrossRefGoogle Scholar
  99. 99.
    Persani L, Rossetti R, Cacciatore C, Bonomi M (2009) Primary Ovarian Insufficiency: X chromosome defects and autoimmunity. J Autoimmun 33:35–41PubMedCrossRefGoogle Scholar
  100. 100.
    Sawalha AH, Harley JB, Scofield RH (2009) Autoimmunity and Klinefelter's syndrome: when men have two X chromosomes. J Autoimmun 33:31–34PubMedCrossRefGoogle Scholar
  101. 101.
    Wells AD (2009) New insights into the molecular basis of T cell anergy: anergy factors, avoidance sensors, and epigenetic imprinting. J Immunol 182:7331–7341PubMedCrossRefGoogle Scholar
  102. 102.
    Zernicka-Goetz M, Morris SA, Bruce AW (2009) Making a firm decision: multifaceted regulation of cell fate in the early mouse embryo. Nat Rev Genet 10:467–477PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2009

Authors and Affiliations

  • Michelle Trenkmann
    • 1
  • Matthias Brock
    • 1
    • 2
  • Caroline Ospelt
    • 1
  • Steffen Gay
    • 1
    • 3
    Email author
  1. 1.Center of Experimental Rheumatology and Zurich Center for Integrative Human Physiology (ZIHP)University of ZurichZurichSwitzerland
  2. 2.Working Group for Pulmonary Hypertension, Department for Internal MedicineUniversity Hospital ZurichZurichSwitzerland
  3. 3.Center of Experimental RheumatologyUniversity Hospital ZurichZurichSwitzerland

Personalised recommendations