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 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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 2-5.
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Accessible chromatin profiles of B cell subsets from healthy and SLE subjectsNCBI Gene Expression Omnibus, GSE118253.
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Effects of biobanking on chromatin accessibilityNCBI Gene Expression Omnibus, GSE71338.
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Transcriptome profiles of B cell subsets from healthy and SLE subjectsNCBI Gene Expression Omnibus, GSE118254.
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Gene expresison studies of lupus and healthy B cell subsets through RNA sequencingNCBI Gene Expression Omnibus, GSE92387.
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DNA methylation profiles profiles of B cell subsets from healthy and SLE subjectsNCBI Gene Expression Omnibus, GSE118255.
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HepG2 Hi-CNCBI Gene Expression Omnibus, GSE113405.
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CHiCAGO: Robust Detection of DNA Looping Interactions in Capture Hi-C dataNCBI Gene Expression Omnibus, GSE81503.
Article and author information
Author details
Funding
HudsonAlpha Institute for biotechnology funds
- Yanfeng Zhang
- Devin M Absher
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2022, Zhang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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