Epigenetic determinants in rheumatoid arthritis: the influence of DNA methylation and histone modifications

REVIEW ARTICLE

Epigenetic determinants in rheumatoid arthritis: the influence of DNA methylation and histone modifications

Bogdan Kolarz 1 , Maria Majdan 2

1. Instytut Fizjoterapii, Wydział Medyczny, Uniwersytet Rzeszowski,
2. Katedra i Klinika Reumatologii i Układowych Chorób Tkanki Łącznej, Uniwersytet Medyczny w Lublinie,

Published: 2017-12-22
DOI: 10.5604/01.3001.0010.7478
GICID: 01.3001.0010.7478
Available language versions: en pl
Issue: Postepy Hig Med Dosw 2017; 71 : 1070-1079

 

Abstract

Epigenetics is a field of science which describes external and environmental modifications to DNA without altering their primary sequences of nucleotides. Contrary to genetic changes, epigenetic modifications are reversible. The epigenetic changes appear as a result of the influence of external factors, such as diet or stress. Epigenetic mechanisms alter the accessibility of DNA by methylation of DNA or post-translational modifications of histones (acetylation, methylation, phosphorylation, ubiquitinqation). The extent of DNA methylation depends on the balance between DNA methyltransferases and demethylases. The main histone modifications are stimulated by K-acetyltransferases, histone deacetylases, K-metyltransferases and K-demethylases. There is proof that environmental modifications of this enzymes regulate immunological processes including autoimmunity in rheumatoid arthritis (RA). In this work we present epigenetic mechanisms involved in RA pathogenesis and a range of research presenting the possible impact of its modification in RA patients.

References

  • 1. Ai R., Whitaker J.W., Boyle D.L., Tak P.P., Gerlag D.M.,Wang W., Firestein G.S.: DNA methylome signature in synoviocytes from patients with early rheumatoid arthritis compared to synoviocytes from patients with longstanding rheumatoid arthritis. Arthritis Rheumatol., 2015; 67: 1978-1980
    Google Scholar
  • 2. Anway M.D., Cupp A.S., Uzumcu M.,Skinner M.K.: Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science, 2005; 308: 1466-1469
    Google Scholar
  • 3. Austenaa L., Barozzi I., Chronowska A., Termanini A., Ostuni R., Prosperini E., Stewart A.F., Testa G., Natoli G.: The histone methyltransferase Wbp7 controls macrophage function through GPI glycolipid anchor synthesis. Immunity, 2012; 36: 572-585
    Google Scholar
  • 4. Bandukwala H.S., Gagnon J., Togher S., Greenbaum J.A., Lamperti E.D., Parr N.J., Molesworth A.M., Smithers N., Lee K., Witherington J., Tough D.F., Prinjha R.K., Peters B., Rao A.: Selective inhibition of CD4+ T-cell cytokine production and autoimmunity by BET protein and c-Myc inhibitors. Proc. Natl. Acad. Sci. USA, 2012; 109: 14532-14537
    Google Scholar
  • 5. Barker D.J., Osmond C., Golding J., Kuh D., Wadsworth M.E.: Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. Br. Med. J., 1989; 298: 564-567
    Google Scholar
  • 6. Bird A.P., Wolffe A.P.: Methylation-induced repression-belts, braces, and chromatin. Cell, 1999; 99: 451-454
    Google Scholar
  • 7. Bozdag M., Dreker T., Henry C., Tosco P., Vallaro M., Fruttero R., Scozzafava A., Carta F., Supuran C.T.: Novel small molecule protein arginine deiminase 4 (PAD4) inhibitors. Bioorg. Med. Chem. Lett., 2013; 23: 715-719
    Google Scholar
  • 8. Bygren L.O., Kaati G., Edvinsson S.: Longevity determined by paternal ancestors’ nutrition during their slow growth period. Acta Biotheor., 2001; 49: 53-59
    Google Scholar
  • 9. Chabane N., Li X., Fahmi H.: HDAC4 contributes to IL-1-induced mPGES-1 expression in human synovial fibroblasts through up-regulation of Egr-1 transcriptional activity. J. Cell. Biochem., 2009; 106: 453-463
    Google Scholar
  • 10. Che K.H.: Development of biochemical tools to characterise human H3K27 histone demethylase JmjD3. University of Oxford; 2013
    Google Scholar
  • 11. Chen Z.J.: Ubiquitin signalling in the NF-κB pathway. Nat. Cell Biol., 2005; 7: 758-765
    Google Scholar
  • 12. Chiang P.K., Gordon R.K., Tal J., Zeng G.C., Doctor B.P., Pardhasaradhi K., McCann P.P.: S-Adenosylmethionine and methylation. FASEB J., 1996; 10: 471-480
    Google Scholar
  • 13. Choo Q.Y., Ho P.C., Tanaka Y., Lin H.S.: Histone deacetylase inhibitors MS-275 and SAHA induced growth arrest and suppressed lipopolysaccharide-stimulated NF-κB p65 nuclear accumulation in human rheumatoid arthritis synovial fibroblastic E11 cells. Rheumatology, 2010; 49: 1447-1460
    Google Scholar
  • 14. Corvetta A., Della Bitta R., Luchetti M.M., Pomponio G.: 5-Methylcytosine content of DNA in blood, synovial mononuclear cells and synovial tissue from patients affected by autoimmune rheumatic diseases. J. Chromatogr., 1991; 566: 481-491
    Google Scholar
  • 15. de Ruijter A.J., van Gennip A.H., Caron H.N., Kemp S., van Kuilenburg A.B.: Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem. J., 2003; 370: 737-749
    Google Scholar
  • 16. De Santa F., Totaro M.G., Prosperini E., Notarbartolo S., Testa G., Natoli G.: The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing. Cell, 2007; 130: 1083-1094
    Google Scholar
  • 17. Deaton A.M., Bird A.: CpG islands and the regulation of transcription. Genes Dev., 2011; 25: 1010-1022
    Google Scholar
  • 18. Denis H., Ndlovu M.N., Fuks F.: Regulation of mammalian DNA methyltransferases: a route to new mechanisms. EMBO Rep., 2011; 12: 647-656
    Google Scholar
  • 19. Dreyton C.J., Jones J.E., Knuckley B.A., Subramanian V., Anderson E.D., Brown S.J., Fernandez-Vega V., Eberhart C., Spicer T., Zuhl A.M., Ferguson J., Speers A.E., Wang C., Boger D.L., Thompson P., Cravatt B.F., Hodder P., Rosen H.: Optimization and characterization of a pan protein arginine deiminase (PAD) inhibitor. Probe Reports from the NIH Molecular Libraries Program, Bethesda (MD) 2010
    Google Scholar
  • 20. Ellis J.A., Munro J.E., Chavez R.A.: Genome-scale case-control analysis of CD4+ T-cell DNA methylation in juvenile idiopathic arthritis reveals potential targets involved in disease. Clin. Epigenetics, 2012; 4: 20
    Google Scholar
  • 21. Feinberg A.P.: Phenotypic plasticity and the epigenetics of human disease. Nature, 2007; 447: 433-440
    Google Scholar
  • 22. Filippakopoulos P., Knapp S.: The bromodomain interaction module. FEBS Lett., 2012; 586: 2692-2704
    Google Scholar
  • 23. Filippakopoulos P., Qi J., Picaud S., Shen Y., Smith W.B., Fedorov O., Morse E.M., Keates T., Hickman T.T., Felletar I., Philpott M., Munro S., McKeown M.R., Wang Y., Christie A.L. i wsp.: Selective inhibition of BET bromodomains. Nature, 2010; 468: 1067-1073
    Google Scholar
  • 24. Gapp K., Jawaid A., Sarkies P., Bohacek J., Pelczar P., Prados J., Farinelli L., Miska E., Mansuy I.M.: Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice. Nat. Neurosci., 2014; 17: 667-669
    Google Scholar
  • 25. Gautschi O., Heighway J., Mack P.C., Purnell P.R., Lara P.N.Jr., Gandara D.R.: Aurora kinases as anticancer drug targets. Clin. Cancer Res., 2008; 14: 1639-1648
    Google Scholar
  • 26. Gay S., Wilson A.G.: The emerging role of epigenetics in rheumatic diseases. Rheumatology, 2014; 53: 406-414
    Google Scholar
  • 27. Gillespie J., Savic S., Wong C., Hempshall A., Inman M., Emery P., Grigg R., McDermott M.F.: Histone deacetylases are dysregulated in rheumatoid arthritis and a novel histone deacetylase 3-selective inhibitor reduces interleukin-6 production by peripheral blood mononuclear cells from rheumatoid arthritis patients. Arthritis Rheum., 2012; 64: 418-422
    Google Scholar
  • 28. Glant T.T., Besenyei T., Kádár A., Kurkó J., Tryniszewska B., Gál J., Soós G., Szekanecz Z., Hoffmann G., Block J.A., Katz R.S., Mikecz K., Rauch T.A.: Differentially expressed epigenome modifiers, including aurora kinases A and B, in immune cells in rheumatoid arthritis in humans and mouse models. Arthritis Rheum., 2013; 65: 1725-1735
    Google Scholar
  • 29. Grabiec A.M., Korchynskyi O., Tak P.P., Reedquist K.A.: Histone deacetylase inhibitors suppress rheumatoid arthritis fibroblast-like synoviocyte and macrophage IL-6 production by accelerating mRNA decay. Ann. Rheum. Dis., 2012; 71: 424-431
    Google Scholar
  • 30. Grabiec A.M., Krausz S., de Jager W., Burakowski T., Groot D., Sanders M.E., Prakken B.J., Maslinski W., Eldering E., Tak P.P., Reedquist K.A.: Histone deacetylase inhibitors suppress inflammatory activation of rheumatoid arthritis patient synovial macrophages and tissue. J. Immunol., 2010; 184: 2718-2728
    Google Scholar
  • 31. Grabiec A.M., Reedquist K.A.: The ascent of acetylation in the epigenetics of rheumatoid arthritis. Nat. Rev. Rheumatol., 2013; 9: 311-318
    Google Scholar
  • 32. Gray S.G.: Epigenetic-based immune intervention for rheumatic diseases. Epigenomics, 2014; 6: 253-271
    Google Scholar
  • 33. Haberland M., Montgomery R.L., Olson E.N.: The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat. Rev. Genet., 2009; 10: 32-42
    Google Scholar
  • 34. Holliday R.: DNA methylation and epigenetic inheritance. Philos. Trans. R. Soc. Lond. B: Biol. Sci., 1990; 326: 329-338
    Google Scholar
  • 35. Horiuchi M., Morinobu A., Chin T., Sakai Y., Kurosaka M., Kumagai S.: Expression and function of histone deacetylases in rheumatoid arthritis synovial fibroblasts. J. Rheumatol., 2009; 36: 1580-1589
    Google Scholar
  • 36. Ishida K., Kobayashi T., Ito S., Komatsu Y., Yokoyama T., Okada M., Abe A., Murasawa A., Yoshie H.: Interleukin-6 gene promoter methylation in rheumatoid arthritis and chronic periodontitis. J. Periodontol., 2012; 83: 917-925
    Google Scholar
  • 37. Jones J.E., Slack J.L., Fang P., Zhang X., Subramanian V., Causey C.P., Coonrod S.A., Guo M., Thompson P.R.: Synthesis and screening of a haloacetamidine containing library to identify PAD4 selective inhibitors. ACS Chem. Biol., 2012; 7: 160-165
    Google Scholar
  • 38. Joosten L.A., Leoni F., Meghji S., Mascagni P.: Inhibition of HDAC activity by ITF2357 ameliorates joint inflammation and prevents cartilage and bone destruction in experimental arthritis. Mol. Med., 2011; 17: 391-396
    Google Scholar
  • 39. Jüngel A., Baresova V., Ospelt C., Simmen B.R., Michel B.A., Gay R.E., Gay S., Seemayer C.A., Neidhart M.: Trichostatin A sensitises rheumatoid arthritis synovial fibroblasts for TRAIL-induced apoptosis. Ann. Rheum. Dis., 2006; 65: 910-912
    Google Scholar
  • 40. Kaati G., Bygren L.O., Edvinsson S.: Cardiovascular and diabetes mortality determined by nutrition during parents› and grandparents› slow growth period. Eur. J. Hum. Genet., 2002; 10: 682-688
    Google Scholar
  • 41. Karouzakis E., Gay R.E., Gay S., Neidhart M.: Epigenetic control in rheumatoid arthritis synovial fibroblasts. Nat. Rev. Rheumatol., 2009; 5: 266-272
    Google Scholar
  • 42. Karouzakis E., Rengel Y., Jüngel A., Kolling C., Gay R.E., Michel B.A., Tak P.P., Gay S., Neidhart M., Ospelt C.: DNA methylation regulates the expression of CXCL12 in rheumatoid arthritis synovial fibroblasts. Genes Immun., 2011; 12: 643-652
    Google Scholar
  • 43. Kawabata T., Nishida K., Takasugi K., Ogawa H., Sada K., Kadota Y., Inagaki J., Hirohata S., Ninomiya Y., Makino H.: Increased activity and expression of histone deacetylase 1 in relation to tumor necrosis factor-alpha in synovial tissue of rheumatoid arthritis. Arthritis Res. Ther., 2010; 12: R133
    Google Scholar
  • 44. Kim Y.I., Logan J.W., Mason J.B., Roubenoff R.: DNA hypomethylation in inflammatory arthritis: reversal with methotrexate. J. Lab. Clin. Med., 1996; 128: 165-172
    Google Scholar
  • 45. Kirsh O., Seeler J.S., Pichler A., Gast A., Müller S., Miska E., Mathieu M., Harel-Bellan A., Kouzarides T., Melchior F., Dejean A.: The SUMO E3 ligase RanBP2 promotes modification of the HDAC4 deacetylase. EMBO J., 2002; 21: 2682-2691
    Google Scholar
  • 46. Klein K., Kabala P.A., Grabiec A.M., Gay R.E., Kolling C., Lin L.L., Gay S., Tak P.P., Prinjha R.K., Ospelt C., Reedquist K.A.: The bromodomain protein inhibitor I-BET151 suppresses expression of inflammatory genes and matrix degrading enzymes in rheumatoid arthritis synovial fibroblasts. Ann. Rheum. Dis., 2016; 75: 422-429
    Google Scholar
  • 47. Klose R.J., Bird A.P.: Genomic DNA methylation: the mark and its mediators. Trends Biochem. Sci., 2006; 31: 89-97
    Google Scholar
  • 48. Kloster M.M., Naderi E.H., Haaland I., Gjertsen B.T., Blomhoff H.K., Naderi S.: cAMP signalling inhibits p53 acetylation and apoptosis via HDAC and SIRT deacetylases. Int. J. Oncol., 2013; 42: 1815-1821
    Google Scholar
  • 49. Knuckley B., Causey C.P., Jones J.E., Bhatia M., Dreyton C.J., Osborne T.C., Takahara H., Thompson P.R.: Substrate specificity and kinetic studies of PADs 1, 3, and 4 identify potent and selective inhibitors of protein arginine deiminase 3. Biochemistry, 2010; 49: 4852-4863
    Google Scholar
  • 50. Kooistra S.M., Helin K.: Molecular mechanisms and potential functions of histone demethylases. Nat. Rev. Mol. Cell Biol., 2012; 13: 297-311
    Google Scholar
  • 51. Kouzarides T.: Chromatin modifications and their function. Cell, 2007; 128: 693-705
    Google Scholar
  • 52. Koziński K., Dobrzyń A.: Wnt signaling pathway – its role in regulation of cell metabolism. Postępy Hig. Med. Dośw., 2013; 67: 1098-1108
    Google Scholar
  • 53. Kruidenier L., Chung C.W., Cheng Z., Liddle J., Che K., Joberty G., Bantscheff M., Bountra C., Bridges A., Diallo H., Eberhard D., Hutchinson S., Jones E., Katso R., Leveridge M. i wsp.: A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature, 2012; 488: 404-408
    Google Scholar
  • 54. Levy D., Kuo A.J., Chang Y., Schaefer U., Kitson C., Cheung P., Espejo A., Zee B.M., Liu C.L., Tangsombatvisit S., Tennen R.I., Kuo A.Y., Tanjing S., Cheung R., Chua K.F. i wsp.: Lysine methylation of the NF-κB subunit RelA by SETD6 couples activity of the histone methyltransferase GLP at chromatin to tonic repression of NF-κB signaling. Nat. Immunol., 2011; 12: 29-36
    Google Scholar
  • 55. Liang J., Lei T., Song Y., Yanes N., Qi Y., Fu M.: RNA-destabilizing factor tristetraprolin negatively regulates NF-κB signaling. J. Biol. Chem., 2009; 284: 29383-29390
    Google Scholar
  • 56. Liao J., Liang G., Xie S., Zhao H., Zuo X., Li F., Chen J., Zhao M., Chan T.M., Lu Q.: CD40L demethylation in CD4+ T cells from women with rheumatoid arthritis. Clin. Immunol., 2012; 145: 13-18
    Google Scholar
  • 57. Lin H.S., Hu C.Y., Chan H.Y., Liew Y.Y., Huang H.P., Lepescheux L., Bastianelli E., Baron R., Rawadi G., Clément-Lacroix P.: Anti-rheumatic activities of histone deacetylase (HDAC) inhibitors in vivo in collagen-induced arthritis in rodents. Br. J. Pharmacol., 2007; 150: 862-872
    Google Scholar
  • 58. Lin S.Y., Hsieh S.C., Lin Y.C., Lee C.N., Tsai M.H., Lai L.C., Chuang E.Y., Chen P.C., Hung C.C., Chen L.Y., Hsieh W.S., Niu D.M., Su Y.N., Ho H.N.: A whole genome methylation analysis of systemic lupus erythematosus: hypomethylation of the IL10 and IL1R2 promoters is associated with disease activity. Genes Immun., 2012; 13: 214-220
    Google Scholar
  • 59. Liu C.C., Fang T.J., Ou T.T., Wu C.C., Li R.N., Lin Y.C., Lin C.H., Tsai W.C., Liu H.W., Yen J.H.: Global DNA methylation, DNMT1, and MBD2 in patients with rheumatoid arthritis. Immunol. Lett., 2011; 135: 96-99
    Google Scholar
  • 60. Liu Y., Aryee M.J., Padyukov L., Fallin M.D., Hesselberg E., Runarsson A., Reinius L., Acevedo N., Taub M., Ronninger M., Shchetynsky K., Scheynius A., Kere J., Alfredsson L., Klareskog L. i wsp.: Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis. Nat. Biotechnol., 2013; 31: 142-147
    Google Scholar
  • 61. Maciejewska-Rodrigues H., Karouzakis E., Strietholt S., Hemmatazad H., Neidhart M., Ospelt C., Gay R.E., Michel B.A., Pap T., Gay S., Jüngel A.: Epigenetics and rheumatoid arthritis: the role of SENP1 in the regulation of MMP-1 expression. J. Autoimmun., 2010; 35: 15-22
    Google Scholar
  • 62. McInnes I.B., Schett G.: Cytokines in the pathogenesis of rheumatoid arthritis. Nat. Rev. Immunol., 2007; 7: 429-442
    Google Scholar
  • 63. Meinecke I., Cinski A., Baier A., Peters M.A., Dankbar B., Wille A., Drynda A., Mendoza H., Gay R.E., Hay R.T., Ink B., Gay S., Pap T.: Modification of nuclear PML protein by SUMO-1 regulates Fas-induced apoptosis in rheumatoid arthritis synovial fibroblasts. Proc. Natl. Acad. Sci. USA, 2007; 104: 5073-5078
    Google Scholar
  • 64. Mele D.A., Salmeron A., Ghosh S., Huang H.R., Bryant B.M., LoraJ.M.: BET bromodomain inhibition suppresses TH17-mediated pathology. J. Exp. Med., 2013; 210: 2181-2190
    Google Scholar
  • 65. Miao C.G., Huang C., Huang Y., Yang Y.Y., He X., Zhang L., Lv X.W., Jin Y., Li J.: MeCP2 modulates the canonical Wnt pathway activation by targeting SFRP4 in rheumatoid arthritis fibroblast-like synoviocytes in rats. Cell. Signal., 2013; 25: 598-608
    Google Scholar
  • 66. Moore D.S. The developing genome: an introduction to behavioral epigenetics: Oxford University Press, 2015
    Google Scholar
  • 67. Morgan H.D., Sutherland H.G., Martin D.I., Whitelaw E.: Epigenetic inheritance at the agouti locus in the mouse. Nat. Genet., 1999; 23: 314-318
    Google Scholar
  • 68. Nakano K., Boyle D.L., Firestein G.S.: Regulation of DNA methylation in rheumatoid arthritis synoviocytes. J. Immunol., 2013; 190: 1297-1303
    Google Scholar
  • 69. Nakano K., Whitaker J.W., Boyle D.L., Wang W., Firestein G.S.: DNA methylome signature in rheumatoid arthritis. Ann. Rheum. Dis., 2013; 72: 110-117
    Google Scholar
  • 70. Nasu Y., Nishida K., Miyazawa S., Komiyama T., Kadota Y., Abe N., Yoshida A., Hirohata S., Ohtsuka A., Ozaki T.: Trichostatin A, a histone deacetylase inhibitor, suppresses synovial inflammation and subsequent cartilage destruction in a collagen antibody-induced arthritis mouse model. Osteoarthritis Cartilage, 2008; 16: 723-732
    Google Scholar
  • 71. Neidhart M., Rethage J., Kuchen S., Künzler P., Crowl R.M., Billingham M.E., Gay R.E., Gay S.: Retrotransposable L1 elements expressed in rheumatoid arthritis synovial tissue: Association with genomic DNA hypomethylation and influence on gene expression. Arthritis Rheum., 2000; 43: 2634-2647
    Google Scholar
  • 72. Nicodeme E., Jeffrey K.L., Schaefer U., Beinke S., Dewell S., Chung C.W., Chandwani R., Marazzi I., Wilson P., Coste H., White J., Kirilovsky J., Rice C.M., Lora J.M., Prinjha R.K. i wsp.: Suppression of inflammation by a synthetic histone mimic. Nature, 2010; 468: 1119-1123
    Google Scholar
  • 73. Niederer F., Ospelt C., Brentano F., Hottiger M.O., Gay R.E., Gay S., Detmar M., Kyburz D.: SIRT1 overexpression in the rheumatoid arthritis synovium contributes to proinflammatory cytokine production and apoptosis resistance. Ann. Rheum. Dis., 2011; 70: 1866-1873
    Google Scholar
  • 74. Nile C.J., Read R.C., Akil M., Duff G.W., Wilson A.G.: Methylation status of a single CpG site in the IL6 promoter is related to IL6 messenger RNA levels and rheumatoid arthritis. Arthritis Rheum., 2008; 58: 2686-2693
    Google Scholar
  • 75. Nishida K., Komiyama T., Miyazawa S., Shen Z.N., Furumatsu T., Doi H., Yoshida A., Yamana J., Yamamura M., Ninomiya Y., Inoue H., Asahara H.: Histone deacetylase inhibitor suppression of autoantibody-mediated arthritis in mice via regulation of p16INK4a and p21WAF1/ Cip1 expression. Arthritis Rheum., 2004; 50: 3365-3376
    Google Scholar
  • 76. Oppermann U.: Why is epigenetics important in understanding the pathogenesis of inflammatory musculoskeletal diseases? Arthritis Res. Ther., 2013; 15: 209
    Google Scholar
  • 77. Osley M.A., Fleming A.B., Kao C.F. Histone ubiquitylation and the regulation of transcription. Results Probl. Cell Differ., 2006: 41: 47-75
    Google Scholar
  • 78. Ospelt C., Gay S.: The role of resident synovial cells in destructive arthritis. Best Pract. Res. Clin. Rheumatol., 2008; 22: 239-252
    Google Scholar
  • 79. Park-Min K.H., Lim E., Lee M.J., Park S.H., Giannopoulou E., Yarilina A., van der Meulen M., Zhao B., Smithers N., Witherington J., Lee K., Tak P.P., Prinjha R.K., Ivashkiv L.B.: Inhibition of osteoclastogenesis and inflammatory bone resorption by targeting BET proteins and epigenetic regulation. Nat. Commun., 2014; 5: 5418
    Google Scholar
  • 80. Petronis A.: Epigenetics as a unifying principle in the aetiology of complex traits and diseases. Nature, 2010; 465: 721-727
    Google Scholar
  • 81. Prinjha R.K., Witherington J., Lee K.: Place your BETs: the therapeutic potential of bromodomains. Trends Pharmacol. Sci., 2012; 33: 146-153
    Google Scholar
  • 82. Ravelli A.C., van der Meulen J.H., Michels R.P., Osmond C., Barker D.J., Hales C.N., Bleker O.P.: Glucose tolerance in adults after prenatal exposure to famine. Lancet, 1998; 351: 173-177
    Google Scholar
  • 83. Richardson B., Scheinbart L., Strahler J., Gross L., Hanash S., Johnson M.: Evidence for impaired T cell DNA methylation in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum., 1990; 33: 1665-1673
    Google Scholar
  • 84. Slack J.L., Causey C.P., Thompson P.R.: Protein arginine deiminase 4: a target for an epigenetic cancer therapy. Cell. Mol. Life Sci., 2011; 68: 709-720
    Google Scholar
  • 85. Sullivan K.E., Reddy A.B., Dietzmann K., Suriano A.R., Kocieda V.P., Stewart M., Bhatia M.: Epigenetic regulation of tumor necrosis factor alpha. Mol. Cell. Biol., 2007; 27: 5147-5160
    Google Scholar
  • 86. Suzuki A., Kochi Y., Shoda H., Seri Y., Fujio K., Sawada T., Yamada R., Yamamoto K.: Decreased severity of experimental autoimmune arthritis in peptidylarginine deiminase type 4 knockout mice. BMC Muscoskelet. Disord., 2016; 17: 205
    Google Scholar
  • 87. Suzuki M.M., Bird A.: DNA methylation landscapes: provocative insights from epigenomics. Nat. Rev. Genet., 2008; 9: 465-476
    Google Scholar
  • 88. Takami N., Osawa K., Miura Y., Komai K., Taniguchi M., Shiraishi M., Sato K., Iguchi T., Shiozawa K., Hashiramoto A., Shiozawa S.: Hypermethylated promoter region of DR3, the death receptor 3 gene, in rheumatoid arthritis synovial cells. Arthritis Rheum., 2006; 54: 779-787
    Google Scholar
  • 89. Tough D.F., Prinjha R.K., Tak P.P.: Epigenetic mechanisms and drug discovery in rheumatology. Clin. Med., 2015; 15 (Suppl. 6): s64-s71
    Google Scholar
  • 90. Trenkmann M., Brock M., Gay R.E., Kolling C., Speich R., Michel B.A., Gay S., Huber L.C.: Expression and function of EZH2 in synovial fibroblasts: epigenetic repression of the Wnt inhibitor SFRP1 in rheumatoid arthritis. Ann. Rheum. Dis., 2011; 70: 1482-1488
    Google Scholar
  • 91. Trenkmann M., Brock M., Ospelt C., Gay S.: Epigenetics in rheumatoid arthritis. Clin. Rev. Allergy Immunol., 2010; 39: 10-19
    Google Scholar
  • 92. Vojinovic J., Damjanov N., D’Urzo C., Furlan A., Susic G., Pasic S., Iagaru N., Stefan M., Dinarello C.A.: Safety and efficacy of an oral histone deacetylase inhibitor in systemic‐onset juvenile idiopathic arthritis. Arthritis Rheum., 2011; 63: 1452-1458
    Google Scholar
  • 93. Vossenaar E.R., Radstake T.R., van der Heijden A., van Mansum M.A., Dieteren C., de Rooij D.J., Barrera P., Zendman A.J., van Venrooij W.J.: Expression and activity of citrullinating peptidylarginine deiminase enzymes in monocytes and macrophages. Ann. Rheum. Dis., 2004; 63: 373-381
    Google Scholar
  • 94. Wang W.L., Lee Y.C., Yang W.M., Chang W.C., Wang J.M.: Sumoylation of LAP1 is involved in the HDAC4-mediated repression of COX-2 transcription. Nucleic Acids Res., 2008; 36: 6066-6079
    Google Scholar
  • 95. Wang Y., Li P., Wang S., Hu J., Chen X.A., Wu J., Fisher M., Oshaben K., Zhao N., Gu Y., Wang D., Chen G., Wang Y.: Anticancer peptidylarginine deiminase (PAD) inhibitors regulate the autophagy flux and the mammalian target of rapamycin complex 1 activity. J. Biol. Chem., 2012; 287: 25941-25953
    Google Scholar
  • 95. Wang Y., Li P., Wang S., Hu J., Chen X.A., Wu J., Fisher M., Oshaben K., Zhao N., Gu Y., Wang D., Chen G., Wang Y.: Anticancer peptidylarginine deiminase (PAD) inhibitors regulate the autophagy flux and the mammalian target of rapamycin complex 1 activity. J. Biol. Chem., 2012; 287: 25941-25953
    Google Scholar
  • 97. Wang Y., Wysocka J., Sayegh J., Lee Y.H., Perlin J.R., Leonelli L., Sonbuchner L.S., McDonald C.H., Cook R.G., Dou Y., Roeder R.G., Clarke S., Stallcup M.R., Allis C.D., Coonrod S.A.: Human PAD4 regulates histone arginine methylation levels via demethylimination. Science, 2004; 306: 279-283
    Google Scholar
  • 98. Weaver I.C., Cervoni N., Champagne F.A., D’Alessio A.C., Sharma S., Seckl J.R., Dymov S., Szyf M., Meaney M.J.: Epigenetic programming by maternal behavior. Nat. Neurosci., 2004; 7: 847-854
    Google Scholar

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