Multiple genetic variants at the SLC30A8 locus affect local super-enhancer activity and influence pancreatic β-cell survival and function

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• dc.contributor.author Hu, Ming
• dc.contributor.author Kim, Innah
• dc.contributor.author Morán, Ignasi
• dc.contributor.author Peng, Weicong
• dc.contributor.author Sun, Orien
• dc.contributor.author Bonnefond, Amélie
• dc.contributor.author Khamis, Amna
• dc.contributor.author Bonàs-Guarch, Silvia
• dc.contributor.author Froguel, Philippe
• dc.contributor.author Rutter, Guy A.
• dc.date.accessioned 2024-08-02T13:57:11Z
• dc.date.available 2024-08-02T13:57:11Z
• dc.date.issued 2024
• dc.description.abstract Variants at the SLC30A8 locus are associated with type 2 diabetes (T2D) risk. The lead variant, rs13266634, encodes an amino acid change, Arg325Trp (R325W), at the C-terminus of the secretory granule-enriched zinc transporter, ZnT8. Although this protein-coding variant was previously thought to be the sole driver of T2D risk at this locus, recent studies have provided evidence for lowered expression of SLC30A8 mRNA in protective allele carriers. In the present study, we examined multiple variants that influence SLC30A8 allele-specific expression. Epigenomic mapping has previously identified an islet-selective enhancer cluster at the SLC30A8 locus, hosting multiple T2D risk and cASE associations, which is spatially associated with the SLC30A8 promoter and additional neighboring genes. Here, we show that deletion of variant-bearing enhancer regions using CRISPR-Cas9 in human-derived EndoC-βH3 cells lowers the expression of SLC30A8 and several neighboring genes and improves glucose-stimulated insulin secretion. While downregulation of SLC30A8 had no effect on beta cell survival, loss of UTP23, RAD21, or MED30 markedly reduced cell viability. Although eQTL or cASE analyses in human islets did not support the association between these additional genes and diabetes risk, the transcriptional regulator JQ1 lowered the expression of multiple genes at the SLC30A8 locus and enhanced stimulated insulin secretion.
• dc.format.mimetype application/pdf
• dc.identifier.citation Hu M, Kim I, Morán I, Peng W, Sun O, Bonnefond A, et al. Multiple genetic variants at the SLC30A8 locus affect local super-enhancer activity and influence pancreatic β-cell survival and function. FASEB J. 2024 Apr 30;38(8):e23610. DOI: 10.1096/fj.202301700RR
• dc.identifier.doi http://dx.doi.org/10.1096/fj.202301700RR
• dc.identifier.issn 0892-6638
• dc.identifier.uri http://hdl.handle.net/10230/60887
• dc.language.iso eng
• dc.publisher Wiley
• dc.relation.ispartof FASEB J. 2024 Apr 30;38(8):e23610
• dc.rights © 2024 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword CRISPR‐Cas9 genome editing
• dc.subject.keyword GWAS
• dc.subject.keyword T2D
• dc.subject.keyword cASE
• dc.subject.keyword Chromatin
• dc.subject.keyword Gene
• dc.subject.keyword Risk variant
• dc.subject.keyword Super‐enhancer
• dc.subject.keyword Transcriptional regulation
• dc.title Multiple genetic variants at the SLC30A8 locus affect local super-enhancer activity and influence pancreatic β-cell survival and function
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion