PAX6 maintains ß cell identity by repressing genes of alternative islet cell types.
J Clin Invest
; 127(1): 230-243, 2017 01 03.
Article
em En
| MEDLINE
| ID: mdl-27941241
ABSTRACT
Type 2 diabetes is thought to involve a compromised ß cell differentiation state, but the mechanisms underlying this dysfunction remain unclear. Here, we report a key role for the TF PAX6 in the maintenance of adult ß cell identity and function. PAX6 was downregulated in ß cells of diabetic db/db mice and in WT mice treated with an insulin receptor antagonist, revealing metabolic control of expression. Deletion of Pax6 in ß cells of adult mice led to lethal hyperglycemia and ketosis that were attributed to loss of ß cell function and expansion of α cells. Lineage-tracing, transcriptome, and chromatin analyses showed that PAX6 is a direct activator of ß cell genes, thus maintaining mature ß cell function and identity. In parallel, we found that PAX6 binds promoters and enhancers to repress alternative islet cell genes including ghrelin, glucagon, and somatostatin. Chromatin analysis and shRNA-mediated gene suppression experiments indicated a similar function of PAX6 in human ß cells. We conclude that reduced expression of PAX6 in metabolically stressed ß cells may contribute to ß cell failure and α cell dysfunction in diabetes.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Cetoacidose Diabética
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Diabetes Mellitus Experimental
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Células Secretoras de Glucagon
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Células Secretoras de Insulina
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Fator de Transcrição PAX6
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Hiperglicemia
Limite:
Animals
Idioma:
En
Revista:
J Clin Invest
Ano de publicação:
2017
Tipo de documento:
Article