An Allele-Specific Functional SNP Associated with Two Systemic Autoimmune Diseases Modulates IRF5 Expression by Long-Range Chromatin Loop Formation

An Allele-Specific Functional SNP Associated with Two Systemic Autoimmune Diseases Modulates IRF5 Expression by Long-Range Chromatin Loop Formation

Both systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) are autoimmune diseases sharing similar genetic backgrounds. Genome-wide association studies have constantly disclosed numerous genetic variants conferring to both disease risks at 7q32.1, but the functional mechanisms underlying t...

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Published in:Journal of investigative dermatology 2020-02, Vol.140 (2), p.348-360.e11
Main Authors: Thynn, Hlaing Nwe, Chen, Xiao-Feng, Hu, Wei-Xin, Duan, Yuan-Yuan, Zhu, Dong-Li, Chen, Hao, Wang, Nai-Ning, Chen, Huan-Huan, Rong, Yu, Lu, Bing-Jie, Yang, Man, Jiang, Feng, Dong, Shan-Shan, Guo, Yan, Yang, Tie-Lin
Format: Article
Language:eng
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Summary:Both systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) are autoimmune diseases sharing similar genetic backgrounds. Genome-wide association studies have constantly disclosed numerous genetic variants conferring to both disease risks at 7q32.1, but the functional mechanisms underlying them are still largely unknown. Through a series of bioinformatics and functional analyses, we prioritized a potential independent functional single-nucleotide polymorphism (rs13239597) within TNPO3 promoter region, residing in a putative enhancer element and validated that IRF5 is the distal target gene (∼118 kb) of rs13239597, which is a key regulator involved in pathogenic autoantibody dysregulation, increasing risk of both SLE and SSc. We experimentally validated the long-range chromatin interactions between rs13239597 and IRF5 using chromosome conformation capture assay. We further demonstrated that rs13239597-A acted as an allele-specific enhancer regulating IRF5 expression, independently of TNPO3 by using dual-luciferase reporter assays and CRISPR-Cas9. Particularly, the transcription factor EVI1 could preferentially bind to rs13239597-A allele and increase the enhancer activity to regulate IRF5 expression. Taken together, our results uncovered a mechanistic insight of a noncoding functional variant acting as an allele-specific distal enhancer to directly modulate IRF5 expression, which might obligate in understanding of complex genetic architectures of SLE and SSc pathogenesis. [Display omitted]
ISSN:0022-202X
1523-1747