Details

Autor(en) / Beteiligte

• Swisa, Avital
• Avrahami, Dana
• Eden, Noa
• Zhang, Jia
• Feleke, Eseye
• Dahan, Tehila
• Cohen-Tayar, Yamit
• Stolovich-Rain, Miri
• Kaestner, Klaus H
• Glaser, Benjamin
• Ashery-Padan, Ruth
• Dor, Yuval

Titel

PAX6 maintains [Beta] cell identity by repressing genes of alternative islet cell types

Ist Teil von

• The Journal of clinical investigation, 2017-01, Vol.127 (1), p.230

Ort / Verlag

Ann Arbor: American Society for Clinical Investigation

Erscheinungsjahr

2017

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Type 2 diabetes is thought to involve a compromised β 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 β cell identity and function. PAX6 was downregulated in β 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 β cells of adult mice led to lethal hyperglycemia and ketosis that were attributed to loss of β cell function and expansion of α cells. Lineage-tracing, transcriptome, and chromatin analyses showed that PAX6 is a direct activator of β cell genes, thus maintaining mature β 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 β cells. We conclude that reduced expression of PAX6 in metabolically stressed β cells may contribute to β cell failure and α cell dysfunction in diabetes.