STAT3-mediated allelic imbalance of novel genetic variant Rs1047643 and B-cell-specific super-enhancer in association with systemic lupus erythematosus
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Curated by eLife
Evaluation Summary:
Zhang and colleagues have conduced extensive multi-omic data analyses and functional assays, aiming to identify novel risk variants and to then explore the potential mechanisms with which the identified variants mediate risk of systemic lupus erythematosus. The findings could advance the understanding of the genetic susceptibility and biology of systemic lupus erythematosus.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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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.
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Evaluation Summary:
Zhang and colleagues have conduced extensive multi-omic data analyses and functional assays, aiming to identify novel risk variants and to then explore the potential mechanisms with which the identified variants mediate risk of systemic lupus erythematosus. The findings could advance the understanding of the genetic susceptibility and biology of systemic lupus erythematosus.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Reviewer #1 (Public Review):
The major strengths of this work include a comprehensive analysis of genetic and functional genomics data, such as chromatin accessibility, DNA methylation, chromatin-chromatin interaction, super enhancer and RNA-seq. The authors have also strengthened their findings through further functional assays in disease target cells. A weakness of this work is a lack of a large-scale genome-wide association study to improve the risk signal.
The authors have identified a novel risk variant, rs1047643, for systemic lupus erythematosus through GWAS together with functional evidence. The identified variant located in a risk locus, 8p23, has been established for the disease. They showed evidence that the identified variant could alter binding affinity of a susceptible factor STAT3 to affect targe genes including a known …
Reviewer #1 (Public Review):
The major strengths of this work include a comprehensive analysis of genetic and functional genomics data, such as chromatin accessibility, DNA methylation, chromatin-chromatin interaction, super enhancer and RNA-seq. The authors have also strengthened their findings through further functional assays in disease target cells. A weakness of this work is a lack of a large-scale genome-wide association study to improve the risk signal.
The authors have identified a novel risk variant, rs1047643, for systemic lupus erythematosus through GWAS together with functional evidence. The identified variant located in a risk locus, 8p23, has been established for the disease. They showed evidence that the identified variant could alter binding affinity of a susceptible factor STAT3 to affect targe genes including a known susceptibility gene BLK for systemic lupus erythematosus. These results provided further support of the functional risk variant discovery. These findings advance the understanding of the genetic susceptibility and biology of systemic lupus erythematosus risk.
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Reviewer #2 (Public Review):
In this manuscript, the authors have conducted several analyses using various omics data to support their conclusion that the SNP (rs1047643) is involved in STAT3-mediated allelic imbalance as well as a B cell specific super enhancer in association with systemic lupus erythematosus.
The analytic pipeline looks reasonable, and the story looks fine for me. I am not an expert in SLE, therefore cannot evaluate the soundness of the biological story.
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Reviewer #3 (Public Review):
1. By mining microarray data and ATAC-seq data, the new functional risk variant rs1047643, located at 8p23, associated with SLE.
2. STAT3-mediated SE activity and the regulatory role of SNP rs1047643 at 8p23 are associated with B-cell deregulation in SLE.
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