To this day, intergenic single nucleotide polymorphisms (SNPs) identified from genome-wide association studies (GWAS) are still a geneticist’s nightmare, because these SNPs are steps away from revealing the disease causative gene, relevant tissue(s), and mechanism of action. For instance, fine mapping and validation of genes causing β cell failure from susceptibility loci identified in type 2 diabetes GWAS poses a significant challenge. The VPS13C-C2CD4A-C2CD4B locus on chromosome 15 confers diabetes susceptibility in every ethnic group studied to date. However, the causative gene is unknown. FoxO1, a transcription factor, is involved in the pathogenesis of β cell dysfunction, but its link to human diabetes GWAS has not been explored. To this end, we generated a genome-wide map of FoxO1 super-enhancers in chemically identified β cells using 2-photon live-cell imaging to monitor FoxO1 localization. Super-enhancers mark genes underpinning β cell identity, and comparing super-enhancers in mouse and human bridge the mouse data to human relevance. When parsed against human super-enhancers and GWAS-derived diabetes susceptibility alleles, this map revealed a conserved super-enhancer in C2CD4A, a gene encoding a β cell/stomach-enriched nuclear protein of unknown function. Genetic ablation of C2cd4a in β cells of mice phenocopied the metabolic abnormalities of human carriers of C2CD4A-linked polymorphisms, resulting in impaired insulin secretion during glucose tolerance tests as well as hyperglycemic clamps. C2cd4a regulates glycolytic genes, and notably represses key β cell “disallowed” genes, such as lactate dehydrogenase A, Aldolase B, and monocarboxylate transporter. We propose that C2CD4A is a transcriptional coregulator of the glycolytic pathway whose dysfunction accounts for the diabetes susceptibility associated with the chromosome 15 GWAS locus.


T. Kuo: None. D. Accili: Board Member; Self; Lilly Diabetes. Other Relationship; Self; Forkhead BioTherapeutics Inc.


National Institutes of Health (K01DK114372)

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