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Identification of C2CD4A as a human diabetes susceptibility gene with a role in β-cell insulin secretion

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE132201 | GEO | 2019/07/31

REPOSITORIES: GEO

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Identification of C2CD4A as a human diabetes susceptibility gene with a role in β-cell insulin secretion [RNA-Seq]

Project description:To investigate the function of C2CD4A, we analyzed RNA profiles in MIN6 cells expressing C2cd4a-GFP or control-GFP.

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Identification of C2CD4A as a human diabetes susceptibility gene with a role in β-cell insulin secretion [ChIP-Seq]

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Identification of C2CD4A as a human diabetes susceptibility gene with a role in ? cell insulin secretion.

Project description:Fine mapping and validation of genes causing ? cell failure from susceptibility loci identified in type 2 diabetes genome-wide association studies (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 is involved in the pathogenesis of ? cell dysfunction, but its link to human diabetes GWAS has not been explored. Here we generated a genome-wide map of FoxO1 superenhancers in chemically identified ? cells using 2-photon live-cell imaging to monitor FoxO1 localization. When parsed against human superenhancers and GWAS-derived diabetes susceptibility alleles, this map revealed a conserved superenhancer in C2CD4A, a gene encoding a ? cell/stomach-enriched nuclear protein of unknown function. Genetic ablation of C2cd4a in ? 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 ? cell "disallowed" genes, such as lactate dehydrogenase A 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.

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Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

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Identification of C2CD4A as a human diabetes susceptibility gene with a role in β-cell insulin secretion

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