期刊
JOURNAL OF INVESTIGATIVE DERMATOLOGY
卷 140, 期 2, 页码 348-360出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jid.2019.06.147
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资金
- National Natural Science Foundation of China, China [31871264, 81573241]
- China Postdoctoral Science Foundation, China [2018T111038]
- Innovative Talent Promotion Plan of Shaanxi Province for Young Sci-Tech New Star, China [2018KJXX-010]
- Zhejiang Provincial Natural Science Foundation of China, China [LGF18C060002]
- Fundamental Research Funds for the Central Universities, China
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 (similar to 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.
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