STAT3-mediated allelic imbalance of novel genetic variant rs1047643 and B cell specific super-enhancer in association with systemic lupus erythematosus
- HudsonAlpha Institute for Biotechnology, United States
- Zymo Research Corp, United States
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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STAT3-mediated allelic imbalance of novel genetic variant rs1047643 and B cell specific super-enhancer in association with systemic lupus erythematosus
eLife 11:e72837.
https://doi.org/10.7554/eLife.72837
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