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Promoter hypermethylation of BCL11B gene correlates with downregulation of gene transcription in ankylosing spondylitis patients

Genes & Immunity volume 18, pages 170–175 (2017)Cite this article

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Abstract

Methylation of DNA is one of the important regulatory mechanisms of gene transcription. B-cell chronic lymphocytic leukemia/lymphoma 11B (BCL11B) plays a key role in the development, proliferation, differentiation, and survival of T cells. The aim of this study was to evaluate promoter methylation of BCL11B gene and its mRNA level in peripheral blood mononuclear cells (PBMCs) of ankylosing spondylitis (AS) patients in relation to healthy controls and evaluate their correlation with diseases clinical indices. Fifty AS patients and 50 healthy controls entered in this study. PBMCs were isolated from whole blood and RNA and DNA contents of leukocytes were extracted. The expression level of BCL11B gene was measured through real-time PCR assay using SYBR Green Master Mix, and PCR products of bisulfite-treated DNA were sequenced to determine the methylation level of promoter. Decreased transcript and increased promoter methylation levels of BCL11B gene were identified in AS patients compared with healthy controls. Hypermethylation of CpG3 and CpG5 was associated with increased AS risk. Promoter hypermethylation and mRNA overexpression correlated with each other but not with clinical manifestations. We identified aberrancies in expression and methylation of BCL11B gene in AS patients compared with healthy control group; however, they might not impress the clinical face of AS.

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References

  1. Gouveia EB, Elmann D, Morales MS . Ankylosing spondylitis and uveitis: overview. Rev Bras Reumatol 2012; 52: 742–756.

    Article  Google Scholar 

  2. Sieper J, Braun J, Rudwaleit M, Boonen A, Zink A . Ankylosing spondylitis: an overview. Ann Rheum Dis 2002; 61 (Suppl 3): iii8–18.

    Article  Google Scholar 

  3. Jamshidi AR, Shahlaee A, Farhadi E, Fallahi S, Nicknam MH, Bidad K et al. Clinical characteristics and medical management of Iranian patients with ankylosing spondylitis. Mod Rheumatol 2014; 24: 499–504.

    Article  Google Scholar 

  4. McVeigh CM, Cairns AP . Diagnosis and management of ankylosing spondylitis. BMJ 2006; 333: 581–585.

    Article  Google Scholar 

  5. Haywood KL, Garratt AM, Dawes PT . Patient-assessed health in ankylosing spondylitis: a structured review. Rheumatology (Oxford, England) 2005; 44: 577–586.

    Article  CAS  Google Scholar 

  6. Shahlaee A, Mahmoudi M, Nicknam MH, Farhadi E, Fallahi S, Jamshidi AR . Gender differences in Iranian patients with ankylosing spondylitis. Clin Rheumatol 2015; 34: 285–293.

    Article  Google Scholar 

  7. Aslani S, Mahmoudi M, Karami J, Jamshidi AR, Malekshahi Z, Nicknam MH . Epigenetic alterations underlying autoimmune diseases. Autoimmunity 2016; 49: 69–83.

    Article  CAS  Google Scholar 

  8. Smith JA . Update on ankylosing spondylitis: current concepts in pathogenesis. Curr Allergy Asthma Rep 2015; 15: 489.

    Article  Google Scholar 

  9. Nicknam MH, Mahmoudi M, Amirzargar AA, Ganjalikhani Hakemi M, Khosravi F, Jamshidi AR et al. Determination of HLA-B27 subtypes in Iranian patients with ankylosing spondylitis. Iran J Allergy Asthma Immunol 2008; 7: 19–24.

    CAS  PubMed  Google Scholar 

  10. Ebrahimi Daryani N, Najmi Varzaneh F, Hedayat M, Taher M, Farhadi E, Mahmoudi M et al. Interleukin-23 receptor single nucleotide polymorphisms in ulcerative colitis. A study in Iranian populations. Clin Res Hepatol Gastroenterol 2014; 38: 360–365.

    Article  CAS  Google Scholar 

  11. Momenzadeh P, Mahmoudi M, Beigy M, Garshasbi M, Vodjdanian M, Farazmand A et al. Determination of IL1 R2, ANTXR2, CARD9, and SNAPC4 single nucleotide polymorphisms in Iranian patients with ankylosing spondylitis. Rheumatol Int 2016; 36: 429–435.

    Article  CAS  Google Scholar 

  12. Mahmoudi M, Jamshidi AR, Amirzargar AA, Farhadi E, Nourijelyani K, Fallahi S et al. Association between endoplasmic reticulum aminopeptidase-1 (ERAP-1) and susceptibility to ankylosing spondylitis in Iran. Iran J Allergy Asthma Immunol 2012; 11: 294–300.

    CAS  PubMed  Google Scholar 

  13. Azizi E, Massoud A, Amirzargar AA, Mahmoudi M, Soleimanifar N, Rezaei N et al. Association of CTLA4 gene polymorphism in Iranian patients with ankylosing spondylitis. J Clin Immunol 2010; 30: 268–271.

    Article  CAS  Google Scholar 

  14. Nicknam MH, Mahmoudi M, Amirzargar AA, Hakemi MG, Khosravi F, Jamshidi AR et al. Determination of HLA-B27 subtypes in Iranian patients with ankylosing spondylitis. Iran J Allergy Asthma Immunol 2008; 7: 19–24.

    CAS  PubMed  Google Scholar 

  15. Jones PA . Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet 2012; 13: 484–492.

    Article  CAS  Google Scholar 

  16. Greer JM, McCombe PA . The role of epigenetic mechanisms and processes in autoimmune disorders. Biologics 2012; 6: 307–327.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Pimentel-Santos FM, Ligeiro D, Matos M, Mourao AF, Costa J, Santos H et al. Whole blood transcriptional profiling in ankylosing spondylitis identifies novel candidate genes that might contribute to the inflammatory and tissue-destructive disease aspects. Arthritis Res Ther 2011; 13: R57.

    Article  Google Scholar 

  18. Huang X, Chen S, Shen Q, Yang L, Li B, Zhong L et al. Analysis of the expression pattern of the BCL11B gene and its relatives in patients with T-cell acute lymphoblastic leukemia. J Hematol Oncol 2010; 3: 44.

    Article  Google Scholar 

  19. Mahmoudi M, Aslani S, Nicknam MH, Karami J, Jamshidi AR . New insights toward the pathogenesis of ankylosing spondylitis; genetic variations and epigenetic modifications. Mod Rheumatol 2017; 27: 198–209.

    Article  Google Scholar 

  20. Brown MA . Genetics of ankylosing spondylitis. Curr Opin Rheumatol 2010; 22: 126–132.

    Article  CAS  Google Scholar 

  21. Daryabor G, Mahmoudi M, Jamshidi A, Nourijelyani K, Amirzargar A, Ahmadzadeh N et al. Determination of IL-23 receptor gene polymorphism in Iranian patients with ankylosing spondylitis. Eur Cytokine Netw 2014; 25: 24–29.

    PubMed  Google Scholar 

  22. Fallahi S, Mahmoudi M, Nicknam MH, Gharibdoost F, Farhadi E, Saei A et al. Effect of HLA-B* 27 and its subtypes on clinical manifestations and severity of ankylosing spondylitis in Iranian patients. Iran J Allergy Asthma Immunol 2013; 12: 321.

    PubMed  Google Scholar 

  23. Mahmoudi M, Jamshidi AR, Amirzargar AA, Farhadi E, Nourijelyani K, Fallahi S et al. Association between endoplasmic reticulum aminopeptidase-1 (ERAP-1) and susceptibility to ankylosing spondylitis in Iran. Iran J Allergy Asthma Immunol 2012; 11: 294.

    CAS  PubMed  Google Scholar 

  24. Soleimanifar N, Amirzargar AA, Mahmoudi M, Pourfathollah AA, Azizi E, Jamshidi AR et al. Study of programmed cell death 1 (PDCD1) gene polymorphims in Iranian patients with ankylosing spondylitis. Inflammation 2011; 34: 707–712.

    Article  Google Scholar 

  25. Quaden DH, De Winter LM, Somers V . Detection of novel diagnostic antibodies in ankylosing spondylitis: an overview. Autoimmun Rev 2016; 15: 820–832.

    Article  CAS  Google Scholar 

  26. Mahmoudi M, Aslani S, Nicknam MH, Karami J, Jamshidi AR . New insights toward the pathogenesis of ankylosing spondylitis; genetic variations and epigenetic modifications. Mod Rheumatol 2016; 27: 1–12.

    Google Scholar 

  27. Selmi C, Lu Q, Humble MC . Heritability versus the role of the environment in autoimmunity. J Autoimmun 2012; 39: 249–252.

    Article  Google Scholar 

  28. Germolec D, Kono DH, Pfau JC, Pollard KM . Animal models used to examine the role of the environment in the development of autoimmune disease: findings from an NIEHS Expert Panel Workshop. J Autoimmun 2012; 39: 285–293.

    Article  Google Scholar 

  29. Ngalamika O, Zhang Y, Yin H, Zhao M, Gershwin ME, Lu Q . Epigenetics, autoimmunity and hematologic malignancies: a comprehensive review. J Autoimmun 2012; 39: 451–465.

    Article  CAS  Google Scholar 

  30. Selmi C, Leung PS, Sherr DH, Diaz M, Nyland JF, Monestier M et al. Mechanisms of environmental influence on human autoimmunity: a national institute of environmental health sciences expert panel workshop. J Autoimmun 2012; 39: 272–284.

    Article  Google Scholar 

  31. Molina V, Shoenfeld Y . Infection, vaccines and other environmental triggers of autoimmunity. Autoimmunity 2005; 38: 235–245.

    Article  CAS  Google Scholar 

  32. Aslani S, Mahmoudi M, Garshasbi M, Jamshidi AR, Karami J, Nicknam MH . Evaluation of DNMT1 gene expression profile and methylation of its promoter region in patients with ankylosing spondylitis. Clin Rheumatol 2016; 35: 2723–2731.

    Article  Google Scholar 

  33. Lai N-S, Chou J-L, Chen GC, Liu S-Q, Lu M-C, Chan MW . Association between cytokines and methylation of SOCS-1 in serum of patients with ankylosing spondylitis. Mol Biol Rep 2014; 41: 3773–3780.

    Article  CAS  Google Scholar 

  34. Chen S, Huang X, Chen S, Yang L, Shen Q, Zheng H et al. The role of BCL11B in regulating the proliferation of human naive T cells. Hum Immunol 2012; 73: 456–464.

    Article  CAS  Google Scholar 

  35. Li L, Leid M, Rothenberg EV . An early T cell lineage commitment checkpoint dependent on the transcription factor Bcl11b. Science 2010; 329: 89–93.

    Article  CAS  Google Scholar 

  36. Cismasiu VB, Adamo K, Gecewicz J, Duque J, Lin Q, Avram D . BCL11B functionally associates with the NuRD complex in T lymphocytes to repress targeted promoter. Oncogene 2005; 24: 6753–6764.

    Article  CAS  Google Scholar 

  37. Cismasiu VB, Ghanta S, Duque J, Albu DI, Chen H-M, Kasturi R et al. BCL11B participates in the activation of IL2 gene expression in CD4+ T lymphocytes. Blood 2006; 108: 2695–2702.

    Article  CAS  Google Scholar 

  38. Califano D, Cho JJ, Uddin MN, Lorentsen KJ, Yang Q, Bhandoola A et al. Transcription factor Bcl11b controls identity and function of mature type 2 innate lymphoid cells. Immunity 2015; 43: 354–368.

    Article  CAS  Google Scholar 

  39. Bartemes KR, Iijima K, Kobayashi T, Kephart GM, McKenzie AN, Kita H . IL-33–responsive lineage− CD25+ CD44hi lymphoid cells mediate innate type 2 immunity and allergic inflammation in the lungs. J Immunol 2012; 188: 1503–1513.

    Article  CAS  Google Scholar 

  40. Wakabayashi Y, Watanabe H, Inoue J, Takeda N, Sakata J, Mishima Y et al. Bcl11b is required for differentiation and survival of αβ T lymphocytes. Nat Immunol 2003; 4: 533–539.

    Article  CAS  Google Scholar 

  41. Zorn E, Nelson EA, Mohseni M, Porcheray F, Kim H, Litsa D et al. IL-2 regulates FOXP3 expression in human CD4+ CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. Blood 2006; 108: 1571–1579.

    Article  CAS  Google Scholar 

  42. Nelson BH . IL-2, regulatory T cells, and tolerance. J Immunol 2004; 172: 3983–3988.

    Article  CAS  Google Scholar 

  43. Maloy KJ, Powrie F . Fueling regulation: IL-2 keeps CD4+ Treg cells fit. Nat Immunol 2005; 6: 1071–1073.

    Article  CAS  Google Scholar 

  44. Jaakkola E, Herzberg I, Laiho K, Barnardo MC, Pointon JJ, Kauppi M et al. Finnish HLA studies confirm the increased risk conferred by HLA-B27 homozygosity in ankylosing spondylitis. Ann Rheum Dis 2006; 65: 775–780.

    Article  CAS  Google Scholar 

  45. Linden SVD, Valkenburg HA, Cats A . Evaluation of diagnostic criteria for ankylosing spondylitis. Arthritis Rheum 1984; 27: 361–368.

    Article  Google Scholar 

  46. Garrett S, Jenkinson T, Kennedy LG, Whitelock H, Gaisford P, Calin A . A new approach to defining disease status in ankylosing spondylitis: the Bath Ankylosing Spondylitis Disease Activity Index. J Rheumatol 1994; 21: 2286–2291.

    CAS  PubMed  Google Scholar 

  47. Calin A, Garrett S, Whitelock H, Kennedy L, O'hea J, Mallorie P et al. A new approach to defining functional ability in ankylosing spondylitis: the development of the Bath Ankylosing Spondylitis Functional Index. J Rheumatol 1994; 21: 2281–2285.

    CAS  PubMed  Google Scholar 

  48. Jenkinson TR, Mallorie PA, Whitelock H, Kennedy LG, Garrett S, Calin A . Defining spinal mobility in ankylosing spondylitis (AS). The Bath AS Metrology Index. J Rheumatol 1994; 21: 1694–1698.

    CAS  PubMed  Google Scholar 

  49. Fallahi S, Jamshidi AR, Bidad K, Qorbani M, Mahmoudi M . Evaluating the reliability of Persian version of ankylosing spondylitis quality of life (ASQoL) questionnaire and related clinical and demographic parameters in patients with ankylosing spondylitis. Rheumatol Int 2014; 34: 803–809.

    Article  Google Scholar 

  50. Bidad K, Fallahi S, Mahmoudi M, Jamshidi A, Farhadi E, Meysamie A et al. Evaluation of the Iranian versions of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Bath Ankylosing Spondylitis Functional Index (BASFI) and the Patient Acceptable Symptom State (PASS) in patients with ankylosing spondylitis. Rheumatol Int 2012; 32: 3613–3618.

    Article  Google Scholar 

  51. Roe BA, Crabtree J, Khan A . Methods for DNA isolation. Part III, Protocols for Recombinant DNA Isolation, Cloning, and Sequencing [Internet edition]. University of Oklahoma: Norman, OK, 1995: pp 2488–2498.

    Google Scholar 

  52. Schmittgen TD, Livak KJ . Analyzing real-time PCR data by the comparative CT method. Nat Protoc 2008; 3: 1101–1108.

    Article  CAS  Google Scholar 

  53. Patterson K, Molloy L, Qu W, Clark S . DNA methylation: bisulphite modification and analysis. J Vis Exp 2011; 56(pii): 3170.

    Google Scholar 

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Acknowledgements

We are deeply grateful to the participants for their contribution in accomplishment of this investigation. The work reported herein was supported by a grant from Deputy of Research, Tehran University of Medical Sciences (Grant No: 93-01-30-24924).

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Authors and Affiliations

  1. Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    J Karami, A Amirzargar, S Aslani & M H Nicknam

  2. Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran

    M Mahmoudi, A Jamshidi & S Aslani

  3. Genetic Department, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

    M Gharshasbi

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Karami, J., Mahmoudi, M., Amirzargar, A. et al. Promoter hypermethylation of BCL11B gene correlates with downregulation of gene transcription in ankylosing spondylitis patients. Genes Immun 18, 170–175 (2017). https://doi.org/10.1038/gene.2017.17

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