STAT3-mediated allelic imbalance of novel genetic variant Rs1047643 and B-cell-specific super-enhancer in association with systemic lupus erythematosus

eLife

Devin M Absher¹  Yanfeng Zhang¹  Kenneth Day² 

[1] HudsonAlpha Institute for Biotechnology, Huntsville, United States;Zymo Research Corp, Irvine, United States;

关键词: allelic imbalance;    super-enhancer;    STAT3;    systemic lupus erythematosus;    b-lymphocyte;    chromatin accessibility;   

DOI  :  10.7554/eLife.72837

来源: DOAJ

【 摘 要 】

Mapping of allelic imbalance (AI) at heterozygous loci has the potential to establish links between genetic risk for disease and biological function. Leveraging multi-omics data for AI analysis and functional annotation, we discovered a novel functional risk variant rs1047643 at 8p23 in association with systemic lupus erythematosus (SLE). This variant displays dynamic AI of chromatin accessibility and allelic expression on FDFT1 gene in B cells with SLE. We further found a B-cell restricted super-enhancer (SE) that physically contacts with this SNP-residing locus, an interaction that also appears specifically in B cells. Quantitative analysis of chromatin accessibility and DNA methylation profiles further demonstrated that the SE exhibits aberrant activity in B cell development with SLE. Functional studies identified that STAT3, a master factor associated with autoimmune diseases, directly regulates both the AI of risk variant and the activity of SE in cultured B cells. Our study reveals that STAT3-mediated SE activity and cis-regulatory effects of SNP rs1047643 at 8p23 locus are associated with B cell deregulation in SLE.

【 授权许可】

Unknown