Genome-Wide DNA Methylation Analysis in Systemic Sclerosis Reveals Hypomethylation of IFN-Associated Genes in CD4+ and CD8+ T Cells

JOURNAL OF INVESTIGATIVE DERMATOLOGY

卷:138

Article

Ding, Weifeng^1,2  Pu, Weilin¹  Wang, Lei³  Jiang, Shuai⁴  Zhou, Xiaodong⁵  Tu, Wenzhen³  Yu, Ling³  Zhang, Jiaqian³  Guo, Shicheng⁶  Liu, Qingmei⁷  Ma, Yanyun⁴  Chen, Sidi¹  Wu, Wenyu⁷  Reveille, John⁵  Zou, Hejian^8,9  Jin, Li¹  Wang, Jiucun^1,9 

[1] Fudan Univ, Sch Life Sci, Collaborat Innovat Ctr Genet & Dev, State Key Lab Genet Engn, Shanghai, Peoples R China

[2] Nantong Univ, Med Lab Ctr, Affiliated Hosp, Nantong, Jiangsu, Peoples R China

[3] Shanghai Tradit Chinese Med Integrated Hosp, Div Rheumatol, Shanghai, Peoples R China

[4] Fudan Univ, Sch Life Sci, Minist Educ, Key Lab Contemporary Anthropol, Shanghai, Peoples R China

[5] Univ Texas Houston, Sch Med, Dept Internal Med, Div Rheumatol, Houston, TX USA

[6] Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA

[7] Fudan Univ, Huashan Hosp, Dept Dermatol, Shanghai, Peoples R China

[8] Fudan Univ, Huashan Hosp, Div Rheumatol, Shanghai, Peoples R China

[9] Fudan Univ, Inst Rheumatol Immunol & Allergy, Shanghai, Peoples R China

DOI  :  10.1016/j.jid.2017.12.003

来源: Elsevier

【 摘 要 】

Epigenetic modifications, including DNA methylation, play an important role in the pathogenesis of autoimmune diseases. In this study, we characterized the DNA methylome in primary T cells of patients with systemic sclerosis. Genome-wide DNA methylation assays of CD4(+) and CD8(+) T cells from 24 systemic sclerosis patients and 24 matched controls were conducted and differentially methylated regions were validated. In the discovery stage, we found that hypomethylation of genes involved in the type I IFN signaling pathway was significantly enriched in both CD4(+) (P = 7.59 x 10(-)6) and CD8(+) (P = 2.10 x 100(-8)) differentially methylated regions. In the validation stage, we confirmed these changes for five type I IFN-associated genes. In addition, protein levels of both type I IFN-alpha (P < 0.0001) and beta (P = 0.002) were significantly elevated in the sera of systemic sclerosis patients. Moreover, significant associations between type I IFN-alpha/beta protein levels with the DNA methylation status as well as the expression profiles of these IFN-associated genes were confirmed. In conclusion, the type I IFN pathway is dysfunctional at the epigenetic level in systemic sclerosis patients, indicating that hypomethylation and upregulation of type I IFN-associated genes might be critical in systemic sclerosis pathogenesis.

【 授权许可】

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