Epigenetics and Behçet’s Disease: DNA Methylation Specially Highlighted

  • Jafar Farhadi Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran AND Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
  • Mohammad Nouri Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
  • Ebrahim Sakhinia Department of Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
  • Nasser Samadi Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
  • Zohreh Babaloo Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
  • Shahriar Alipour Mail Department of Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
  • Golamreza Jadideslam Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran AND Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran AND Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
  • Farhad Pouremamali Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
  • Alireza Khabbazi Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
Behcet’s disease, DNA methylation, Epigenetics


Behçet's disease (BD) is a multisystem inflammatory disease with unknown etiology. Although evidence about the pathogenesis of BD is growing, the actual cause of this disease is unclear. Both genetic and epigenetic factors are claimed to play significant roles in BD. Epigenetic factors such as age, gender, smoking as well as exogenous factors like diet, infection, stress are related to the onset and clinical manifestations of BD. DNA methylation refers to a major epigenetic element which influences gene activities with catalyzing DNA using a set of DNA methyltransferases (Dnmts). DNA methylation status of many genes in patients with BD is different from that of healthy people. For example, cytoskeletal gene, Human Leukocyte Antigen (HLA) loci, Long interspersed nuclear element (LINE-1), and Arthrobacter luteus (Alu) repetitive sequences are different in the DNA methylation status in patients with BD and healthy controls. In this paper we reviewed, according to previous studies, the mechanisms of epigenetic, the epigenetic factors involved in the BD, and especially the effect of DNA methylation in the Behcet’s disease. Future studies are needed to identify the capability of specific DNA methylation alterations in BD in order to predict disease manifestations, medical course, and response to treatment.


1. Alipour S, Nouri M, Khabbazi A, Samadi N, Babaloo Z, Abolhasani S, et al. Hypermethylation of IL-10 gene is responsible for its low mRNA expression in Behcet's disease. JCell Biochem 2018; 119(8):6614-22.
2. Hirohata S, Kikuchi H. Behçet's disease. Arthritis Res Ther 2003; 5(3):139-46.
3. Saadoun D, Wechsler B. Behçet's disease. Orphanet J Rare Dis. 2012; 7(1):20.
4. Demirelli S, Degirmenci H, Inci S, Arisoy A. Cardiac manifestations in Behcet's disease. Intractable Rare Dis Res 2015; 4(2):70-5.
5. Guerrero-Preston R, Herbstman J, Goldman LR. Epigenomic biomonitors: global DNA hypomethylation as a biodosimeter of life-long environmental exposures. Epigenomics2011; 3(1):1-5.
6. Romani M, Pistillo MP, Banelli B. Environmental epigenetics: crossroad between public health, lifestyle,and cancer prevention. BioMed Res Intl 2015; 2015:587983.
7. Moore LD, Le T, Fan G. DNA methylation and its basic function. Neuropsychopharmacology. 2013; 38(1):23-38.
8. Gupta R, Nagarajan A, Wajapeyee N. Advances in genome-wide DNA methylation analysis. Biotechniques 2010; 49(4):iii-xi.
9. Elbjeirami WM. DNA Methylation in the Inflammatory Response and Relevance to Chronic Kidney Disease.
10. Jung M, Pfeifer GP. Aging and DNA methylation. BMC biol 2015; 13(1):7.
11. Alipour S, Nouri M, Khabbazi A, Samadi N, Babaloo Z, Abolhasani S, et al. Hypermethylation of IL‐10 gene is responsible for its low mRNA expression in Behçet's disease. J Cell Biochem 2018; 119(8):6614-22.
12. Alipour S, Sakhinia E, Khabbazi A, Samadi N, Babaloo Z, Azad M, et al. Methylation Status of Interleukin-6 Gene Promoter in Patients with Behçet's Disease. Reumatol Clin 2018.
13. Fradin D, Le Fur S, Mille C, Naoui N, Groves C, Zelenika D, et al. Association of the CpG methylation pattern of the proximal insulin gene promoter with type 1 diabetes. PloS one 2012; 7(5):e36278.
14. Belot MP, Fradin D, Mai N, Le Fur S, Zelenika D, Kerr-Conte J, et al. CpG methylation changes within the IL2RA promoter in type 1 diabetes of childhood onset. PloS one 2013; 8(7):e68093.
15. Gu T, Falhammar H, Gu HF, Brismar K. Epigenetic analyses of the insulin-like growth factor binding protein 1 gene in type 1 diabetes and diabetic nephropathy. ClinEpigenetics 2014;6(1):10.
16. Deng C, Kaplan MJ, Yang J, Ray D, Zhang Z, McCune WJ, et al. Decreased Ras-mitogen-activated protein kinase signaling may cause DNA hypomethylation in T lymphocytes from lupus patients. Arthritis Rheum 2001; 44(2):397-407.
17. Gorelik G, Richardson B. Aberrant T cell ERK pathway signaling and chromatin structure in lupus. Autoimmunity Rev 2009; 8(3):196-8.
18. Sunahori K, Juang YT, Kyttaris VC, Tsokos GC. Promoter hypomethylation results in increased expression of protein phosphatase 2A in T cells from patients with systemic lupus erythematosus. J Immunol2011; 186(7):4508-17.
19. Zhao M, Sun Y, Gao F, Wu X, Tang J, Yin H, et al. Epigenetics and SLE: RFX1 downregulation causes CD11a and CD70 overexpression by altering epigenetic modifications in lupus CD4+ T cells. JAutoimmun 2010; 35(1):58-69.
20. Lu Q, Wu A, Richardson BC. Demethylation of the same promoter sequence increases CD70 expression in lupus T cells and T cells treated with lupus-inducing drugs. J Immunol 2005; 174(10):6212-9.
21. Li Y, Zhao M, Yin H, Gao F, Wu X, Luo Y, et al. Overexpression of the growth arrest and DNA damage-induced 45alpha gene contributes to autoimmunity by promoting DNA demethylation in lupus T cells. Arthritis Rheum 2010; 62(5):1438-47.
22. Li Y, Huang C, Zhao M, Liang G, Xiao R, Yung S, et al. A possible role of HMGB1 in DNA demethylation in CD4+ T cells from patients with systemic lupus erythematosus. Clin Dev Immunol 2013; 2013:206298.
23. Kaplan MJ, Lu Q, Wu A, Attwood J, Richardson B. Demethylation of promoter regulatory elements contributes to perforin overexpression in CD4+ lupus T cells. J Immunol 2004; 172(6):3652-61.
24. Lu Q, Wu A, Tesmer L, Ray D, Yousif N, Richardson B. Demethylation of CD40LG on the inactive X in T cells from women with lupus. J Immunol 2007; 179(9):6352-8.
25. Lal G, Zhang N, van der Touw W, Ding Y, Ju W, Bottinger EP, et al. Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. J Immunol 2009; 182(1):259-73.
26. Zhao M, Tang J, Gao F, Wu X, Liang Y, Yin H, et al. Hypomethylation of IL10 and IL13 promoters in CD4+ T cells of patients with systemic lupus erythematosus. J BiomedBiotechnol 2010; 2010:931018.
27. Nile CJ, Read RC, Akil M, Duff GW, Wilson AG. 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(9):2686-93.
28. Fu LH, Ma CL, Cong B, Li SJ, Chen HY, Zhang JG. Hypomethylation of proximal CpG motif of interleukin-10 promoter regulates its expression in human rheumatoid arthritis. Acta pharmacol Sin 2011;32(11):1373-80.
29. Takami N, Osawa K, Miura Y, Komai K, Taniguchi M, Shiraishi M, et al. Hypermethylated promoter region of DR3, the death receptor 3 gene, in rheumatoid arthritis synovial cells. Arthritis Rheum 2006; 54(3):779-87.
30. Karouzakis E, Rengel Y, Jungel A, Kolling C, Gay RE, Michel BA, et al. DNA methylation regulates the expression of CXCL12 in rheumatoid arthritis synovial fibroblasts. Genes Immun 2011; 12(8):643-52.
31. Karouzakis E, Trenkmann M, Gay RE, Michel BA, Gay S, Neidhart M. Epigenome analysis reveals TBX5 as a novel transcription factor involved in the activation of rheumatoid arthritis synovial fibroblasts. J Immunol 2014; 193(10):4945-51.
32. Fukuhara T, Tomiyama T, Yasuda K, Ueda Y, Ozaki Y, Son Y, et al. Hypermethylation of MST1 in IgG4-related autoimmune pancreatitis and rheumatoid arthritis. BiochemBiophys Res Commun 2015; 463(4):968-74.
33. Cribbs AP, Kennedy A, Penn H, Amjadi P, Green P, Read JE, et al. Methotrexate Restores Regulatory T Cell Function Through Demethylation of the FoxP3 Upstream Enhancer in Patients With Rheumatoid Arthritis. Arthritis Rheumatol 2015; 67(5):1182-92.
34. Kennedy A, Schmidt EM, Cribbs AP, Penn H, Amjadi P, Syed K, et al. A novel upstream enhancer of FOXP3, sensitive to methylation-induced silencing, exhibits dysregulated methylation in rheumatoid arthritis Treg cells. Eur J Immunol 2014; 44(10):2968-78.
35. Kojima A, Kobayashi T, Ito S, Murasawa A, Nakazono K, Yoshie H. Tumor necrosis factor-alpha gene promoter methylation in Japanese adults with chronic periodontitis and rheumatoid arthritis. J Periodontal Res 2016; 51(3):350-8.
36. Kumagai C, Kalman B, Middleton FA, Vyshkina T, Massa PT. Increased promoter methylation of the immune regulatory gene SHP-1 in leukocytes of multiple sclerosis subjects. J Neuroimmunol2012; 246(1-2):51-7.
37. Mastronardi FG, Noor A, Wood DD, Paton T, Moscarello MA. Peptidyl argininedeiminase 2 CpG island in multiple sclerosis white matter is hypomethylated. JNeurosci Res 2007; 85(9):2006-16.
38. Perron H, Lang A. The human endogenous retrovirus link between genes and environment in multiple sclerosis and in multifactorial diseases associating neuroinflammation. Clin RevAllergy Immunol 2010; 39(1):51-61.
39. Calabrese R, Valentini E, Ciccarone F, Guastafierro T, Bacalini MG, Ricigliano VA, et al. TET2 gene expression and 5-hydroxymethylcytosine level in multiple sclerosis peripheral blood cells. Biochim Biophys Acta 2014; 1842(7):1130-6.
40. Graves MC, Benton M, Lea RA, Boyle M, Tajouri L, Macartney-Coxson D, et al. Methylation differences at the HLA-DRB1 locus in CD4+ T-Cells are associated with multiple sclerosis. MultScler 2014;20(8):1033-41.
41. Gowers IR, Walters K, Kiss-Toth E, Read RC, Duff GW, Wilson AG. Age-related loss of CpG methylation in the tumour necrosis factor promoter. Cytokine 2011; 56(3):792-7.
42. Alipour S, Nouri M, Sakhinia E, Samadi N, Roshanravan N, Ghavami A, et al. Epigenetic alterations in chronic disease focusing on Behçet’s disease. Biomed Pharmacother2017; 91:526-33.
43. Issa J-PJ, Ahuja N, Toyota M, Bronner MP, Brentnall TA. Accelerated age-related CpG island methylation in ulcerative colitis. Cancer Res 2001; 61(9):3573-7.
44. Li Z, Liu C, Xie Z, Song P, Zhao RC, Guo L, et al. Epigenetic dysregulation in mesenchymal stem cell aging and spontaneous differentiation. PloS one 2011; 6(6):e20526.
45. Jintaridth P, Mutirangura A. Distinctive patterns of age-dependent hypomethylation in interspersed repetitive sequences. PhysiolGenomics 2010; 41(2):194-200.
46. Houman M, Neffati H, Braham A, Harzallah O, Khanfir M, Miled M, et al. Behçet's disease in Tunisia. Demographic, clinical and genetic aspects in 260 patients. ClinExp Rheumatol 2007; 25(4 Suppl 45):S58-64.
47. Hamzaoui A, Jaziri F, Salem TB, Ghorbel FSIB, Lamloum M, Khanfir MS, et al. Comparison of clinical features of Behcet disease according to age in a Tunisian cohort. Acta Med Iran 2014; 52(10):748.
48. Hazirolan D, Sungur G, Duman S. Demographic, clinical, and ocular features in patients with late-onset Behçet disease. Ocul Immunol Inflamm2012; 20(2):119-24.
49. Lee KW, Pausova Z. Cigarette smoking and DNA methylation. Front Genet 2013; 4:132.
50. Pollard KM. Gender differences in autoimmunity associated with exposure to environmental factors. Jautoimmun 2012; 38(2):J177-J86.
51. Tursen U, Gurler A, Boyvat A. Evaluation of clinical findings according to sex in 2313 Turkish patients with Behçet's disease. Int JDermatol 2003;42(5):346-51.
52. Nussinovitch U, Shoenfeld Y. The role of gender and organ specific autoimmunity. Autoimmun Rev 2012;11(6):A377-A85.
53. Bang D, Oh S, Lee K-H, Lee E-S, Lee S. Influence of sex on patients with Behçet’s disease in Korea. Adv Exp Med Biol2003; 528:59-63.
54. Mumcu G, Inanc N, Aydin S, Ergun T, Direskeneli H. Association of salivary S. mutans colonisation and mannose-binding lectin deficiency with gender in Behçet's disease. Clin Exp Rheumatol 2009; 27(2):S32-6.
55. Bilgin AB, Turkoglu EB, Ilhan HD, Unal M, Apaydin KC. Is smoking a risk factor in ocular Behçet disease? Ocul Immunol Inflamm 2015; 23(4):283-6.
56. Alberg AJ. Cigarette smoking: health effects and control strategies. Drugs Today (Barc) 2008; 44(12):895-904.
57. Cheng A, Pang C, Leung A, Chua J, Fan D, Lam D. The association between cigarette smoking and ocular diseases. Hong Kong Med J 2000; 6(2):195-202.
58. Roesel M, Ruttig A, Schumacher C, et al. Smoking complicates the course of non-infectious uveitis. Graefes ArcClin Exp Ophthalmol 2011; 249(6):903-7.
59. Orosz Z, Csiszar A, Labinskyy N, Smith K, Kaminski PM, Ferdinandy P, et al. Cigarette smoke-induced proinflammatory alterations in the endothelial phenotype: role of NAD (P) H oxidase activation. Am J Physiol Heart Circ Physiolo 2007; 292(1):H130-H9.
60. Kaklamani VG, Tzonou A, Markomichelakis N, Papazoglou S, Kaklamanis PG. The effect of smoking on the clinical features of Adamantiades-Behcet’s disease. Adv Exp Med Biol 2004; 528:323-7.
61. Aramaki K, Kikuchi H, Hirohata S. HLA-B51 and cigarette smoking as risk factors for chronic progressive neurological manifestations in Behçet's disease. Mod Rheumatol 2007; 17(1):81-2.
62. Invernizzi P, Pasini S, Selmi C, Gershwin ME, Podda M. Female predominance and X chromosome defects in autoimmune diseases. JAutoimmun 2009; 33(1):12-6.
63. Takada H, Nomura A, Ishimura M, Ichiyama M, Ohga S, Hara T. NEMO mutation as a cause of familial occurrence of Behçet's disease in female patients. Clin Genet 2010; 78(6):575-9.
64. Suzuki N, Sakane T, Ueda Y, Tsunematsu T. Abnormal B cell function in patients with Behçet's disease. Arthritis Rheum 1986; 29(2):212-9.
65. Volle G, Fraison JB, Gobert D, Goulenok T, Dhote R, Fain O, et al. Dietary and Non‐Dietary Triggers of Oral Ulcer Recurrences in Behçet's Disease. Arthritis care Res 2017; 69(9):1429-36.
66. Hirahara K, Nakayama T. CD4+ T-cell subsets in inflammatory diseases: beyond the T h 1/T h 2 paradigm. Int immuno2016;28(4):163-71.
67. Hughes T, Ture‐Ozdemir F, Alibaz‐Oner F, Coit P, Direskeneli H, Sawalha AH. Epigenome‐Wide Scan Identifies a Treatment‐Responsive Pattern of Altered DNA Methylation Among Cytoskeletal Remodeling Genes in Monocytes and CD4+ T Cells From Patients With Behçet's Disease. Arthritis Rheum2014; 66(6):1648-58.
68. Jorizzo JL, Hudson RD, Schmalstieg FC, Daniels JC, Apisarnthanarax P, Henry JC, et al. Behçet's syndrome: immune regulation, circulating immune complexes, neutrophil migration, and colchicine therapy. J Am AcadDermatol1984; 10(2):205-14.
69. Renauer P, Coit P, Sawalha AH. Epigenetics and vasculitis: a comprehensive review. Clin Rev allergy Immunol2016; 50(3):357-66.
70. Morton LT, Situnayake D, Wallace GR. Genetics of Behçet's disease. Curr Opin Rheumatol 2016; 28(1):39-44.
71. Jansen S, Collins A, Yang C, Rebowski G, Svitkina T, Dominguez R. Mechanism of actin filament bundling by fascin. JBiol Chem 2011; 286(34):30087-96.
72. Zanet J, Jayo A, Plaza S, Millard T, Parsons M, Stramer B. Fascin promotes filopodia formation independent of its role in actin bundling. J Cell Biol 2012; 197(4):477-86.
73. Millard TH, Dawson J, Machesky LM. Characterisation of IRTKS, a novel IRSp53/MIM family actin regulator with distinct filament bundling properties. J Cell scie 2007; 120(9):1663-72.
74. Sudhaharan T, Sem KP, Liew HF, Yu YH, Goh WI, Chou AM, et al. The Rho GTPase Rif signals through IRTKS, Eps8 and WAVE2 to generate dorsal membrane ruffles and filopodia. J Cell Sci 2016; 129(14):2829-40.
75. Xia P, Wang S, Xiong Z, Ye B, Huang L-Y, Han Z-G, et al. IRTKS negatively regulates antiviral immunity through PCBP2 sumoylation-mediated MAVS degradation. Nat communi. 2015; 6:8132.
76. Sawada N, Li Y, Liao JK. Novel aspects of the roles of Rac1 GTPase in the cardiovascular system. Curr OpinPharmacol. 2010; 10(2):116-21.
77. Zhong CQ, Li Y, Yang D, Zhang N, Xu X, Wu Y, et al. Quantitative phosphoproteomic analysis of RIP3‐dependent protein phosphorylation in the course of TNF‐induced necroptosis. Proteomics 2014; 14(6):713-24.
78. Wu X, Tian L, Li J, Zhang Y, Han V, Li Y, et al. Investigation of receptor interacting protein (RIP3)-dependent protein phosphorylation by quantitative phosphoproteomics. Mol Cell Proteomics 2012; 11(12):1640-51.
79. Sala-Valdés M, Gordón-Alonso M, Tejera E, Ibáñez A, Cabrero JR, Ursa A, et al. Association of syntenin-1 with M-RIP polarizes Rac-1 activation during chemotaxis and immune interactions. J Cell Sci 2012; 125(5):1235-46.
80. Chuang Y, Xu X, Kwiatkowska A, Tsapraillis G, Hwang H, Petritis K, et al. Regulation of synaptojanin 2 5′-phosphatase activity by Src. Cell Adh Migr 2012; 6(6):518-25.
81. Kontrogianni-Konstantopoulos A, Catino DH, Strong JC, Randall WR, Bloch RJ. Obscurin regulates the organization of myosin into A bands. Am J Physiol Cell Physiol 2004; 287(1):C209-C17.
82. Yüksel Ş, Kucukazman SO, Karataş GS, Ozturk MA, Prombhul S, Hirankarn N. Methylation status of alu and LINE-1 interspersed repetitive sequences in Behcet’s disease patients. BioMed Res Int 2016; 2016:1393089.
83. Forster VJ, McDonnell A, Theobald R, McKay JA. Effect of methotrexate/vitamin B12 on DNA methylation as a potential factor in leukemia treatment-related neurotoxicity. Epigenomics 2017; 9(9):1205-18.
84. 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.
85. Goud Alladi C, Etain B, Bellivier F, Marie-Claire C. DNA Methylation as a Biomarker of Treatment Response Variability in Serious Mental Illnesses: A Systematic Review Focused on Bipolar Disorder, Schizophrenia, and Major Depressive Disorder. Int JMol Sci 2018; 19(10):3026.
How to Cite
Farhadi J, Nouri M, Sakhinia E, Samadi N, Babaloo Z, Alipour S, Jadideslam G, Pouremamali F, Khabbazi A. Epigenetics and Behçet’s Disease: DNA Methylation Specially Highlighted. Iran J Allergy Asthma Immunol. 18(5):462-472.
Review Article(s)