ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2024
Multiple genetic variants at the SLC30A8 locus affect local super-enhancer activity and influence pancreatic β-cell survival and function.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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8 citing papers in PubMed, 7 citations in OpenAlex.
- SLC30A8 (ZnT8) at the crossroads of epigenetics and microRNA regulation in type 2 diabetes and nephropathy.World journal of nephrology · 2026Review
- Article
- ZDHHC8-mediated S-palmitoylation of RAD21 causes mitochondrial dysfunction in diabetic nephropathy via inhibiting ACSM3 transcription.Cell death and differentiation · 2026Article
- MiRNAs in hyperglycemia-induced metabolic memory: established mechanisms and emerging nuclear activation concepts.Diabetology & metabolic syndrome · 2026Review
- I-BET151 modulates glucokinase gene expression and beta cell function in part through changes in FOXO1 expression.Diabetologia · 2025Article
- The SLC-ome of membrane transport: From molecular discovery to physiology and clinical applications.Physiological reviews · 2025Review
- β-cell dedifferentiation in type 2 diabetes: Interplay of metabolic stress, endoplasmic reticulum dysfunction, and forkhead box protein O1 inhibition.World journal of diabetes · 2025Article
- Placental Expression of Glucose and Zinc Transporters in Women with Gestational Diabetes.Journal of clinical medicine · 2024Article
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10 authors at 5 institutions in 5 countries.
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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.
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