Identification of C2CD4A as a human diabetes susceptibility gene with a role in ß cell insulin secretion.
Proc Natl Acad Sci U S A
; 116(40): 20033-20042, 2019 10 01.
Article
em En
| MEDLINE
| ID: mdl-31527256
ABSTRACT
Fine mapping and validation of genes causing ß 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 ß 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 ß 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 ß cell/stomach-enriched nuclear protein of unknown function. Genetic ablation of C2cd4a in ß 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 ß 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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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
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Variação Genética
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Proteínas Nucleares
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Predisposição Genética para Doença
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Diabetes Mellitus Tipo 2
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Células Secretoras de Insulina
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Insulina
Tipo de estudo:
Diagnostic_studies
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Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article