STAT3-mediated allelic imbalance of novel genetic variant rs1047643 and B cell specific super-enhancer in association with systemic lupus erythematosus

Abstract

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 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 open chromatin 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.

Construction of molecular subgroups in childhood systemic lupus erythematosus using bioinformatics

“…[25] STAT3 is activated by phosphorylation of tyrosine 705 and/or serine 727, and phosphorylated STAT3 can bind target sequences in promoter regions to regulate gene transcription. [26] Recently, elevated STAT3 levels in SLE have attracted increased attention. Arakawa et al [27] detected a significantly increased expression of STAT3 and phosphorylated STAT3 in the kidneys of patients with LN.…”