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Abstract Number: 1727

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

Weilin Pu1, Weifeng Ding2, Lei Wang3, Shuai Jiang4, Wenzhen Tu3, Shicheng Guo5, Qingmei Liu6, Yanyun Ma4, Sidi Chen7, Wenyu Wu6, Xiaodong Zhou8, Maureen D. Mayes9, Shervin Assassi9, John D. Reveille9, Li Jin10 and Jiucun Wang10, 1State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences,, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, China, Shanghai, China, 2Medical Laboratory Center, Medical Laboratory Center, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China, Nantong, China, 3Division of Rheumatology, Division of Rheumatology, Shanghai TCM-integrated Hospital, Shanghai, China, Shanghai, China, 4Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China, Shanghai, China, 5Department of Bioengineering, Department of Bioengineering, University of California at San Diego, CA, USA, San Diego, CA, 6Department of Dermatology, Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China, Shanghai, China, 7State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences,, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, China, Shanghai, China, 8Internal Medicine-Rheumatology, University of Texas McGovern Medical School, Houston, TX, 9University of Texas McGovern Medical School, Houston, TX, 10State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, China, Shanghai, China

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: CD T cells, DNA Methylation, Epigenetics, interferons and systemic sclerosis

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Session Information

Date: Monday, November 6, 2017

Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's – Pathogenesis, Animal Models and Genetics Poster II

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose: Systemic sclerosis (SSc) is a complex systemic autoimmune disease caused by complicated interaction between genetic, epigenetic and environmental risk factors. Evidence showed epigenetic modifications, including DNA methylation, play an important part in the regulation of gene expression and the pathogenesis of a large number of autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, variations of DNA methylation in SSc have not been comprehensively investigated, especially for subtypes of the immune cells separately. To examine the methylation status in CD4+ and CD8+ T cells of SSc, we performed genome-wide DNA methylation microarray study in Chinese SSc patients and matched controls.

Methods: CD4+ and CD8+ T cells were obtained from SSc patients (n =24) and from age- and sex-matched healthy controls (n =24). All patients met the 2013 criteria for SSc established by the ACR/EULAR. Illumina Infinium HumanMethylation450 BeadChip was utilized for DNA quantification. The significantly differentially methylated sites (DMS) were validated using targeted bisulfite sequencing in an extended cohort consisting of 43 SSc patients and 41 controls (including 12 cases and 12 controls from the initial group). The expression profiles of the differentially methylated genes were measured by RT-PCR. In addition, the serum level of type I interferon-alpha/beta in SSc patients and controls was also quantified by ELISA.

 

Results: In the discovery stage, type I interferon (IFN)-associated genes were significantly hypomethylated and type I IFN signaling pathway was most significantly enriched in both CD4+ and CD8+ T cells of SSc patients compared to controls, suggesting an abnormality of the type I IFN pathway in SSc patients (Fig 1-A, B). In the second stage, the significantly hypomethylation status of five type I IFN-associated genes (EIF2AK2, IFI44L, IFITM1, MX1, PARP9) was validated (by targeted bisulfite sequencing). Moreover, the upregulation of these genes was also shown in both CD4+ CD8+ T cells of SSc patients (by RT-PCR) (Fig 1-C, D). Further, the serum levels of type I IFN-alpha/beta were also elevated in SSc patients over controls (by ELISA) (Fig 1-E, F). The significant correlations between gene expression, DNA methylation and serum level of type I IFN-alpha/beta were also confirmed, though showing different patterns between CD4+ and CD8+ T cells.

Conclusion: Hypomethylation and upregulation of type I IFN-associated genes were observed in both CD4+ and CD8+ T cells of SSc patients. The serum level of type I IFN-alpha/beta was elevated in SSc patients and correlated significantly with the methylation and expression of its associated genes. It is suggested that hypomethylation of type I IFN-associated genes may be involved in the pathogenesis of SSc. 


Disclosure: W. Pu, None; W. Ding, None; L. Wang, None; S. Jiang, None; W. Tu, None; S. Guo, None; Q. Liu, None; Y. Ma, None; S. Chen, None; W. Wu, None; X. Zhou, None; M. D. Mayes, None; S. Assassi, None; J. D. Reveille, None; L. Jin, None; J. Wang, None.

To cite this abstract in AMA style:

Pu W, Ding W, Wang L, Jiang S, Tu W, Guo S, Liu Q, Ma Y, Chen S, Wu W, Zhou X, Mayes MD, Assassi S, Reveille JD, Jin L, Wang J. Genome-Wide DNA Methylation Analysis in Systemic Sclerosis Reveals Hypomethylation of Interferon-Associated Genes in CD4+ and CD8+ T Cells [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/genome-wide-dna-methylation-analysis-in-systemic-sclerosis-reveals-hypomethylation-of-interferon-associated-genes-in-cd4-and-cd8-t-cells/. Accessed .
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