Title |
PAX6 maintains β cell identity by repressing genes of alternative islet cell types
|
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Published in |
Journal of Clinical Investigation, December 2016
|
DOI | 10.1172/jci88015 |
Pubmed ID | |
Authors |
Avital Swisa, Dana Avrahami, Noa Eden, Jia Zhang, Eseye Feleke, Tehila Dahan, Yamit Cohen-Tayar, Miri Stolovich-Rain, Klaus H. Kaestner, Benjamin Glaser, Ruth Ashery-Padan, Yuval Dor |
Abstract |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
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France | 1 | 10% |
Canada | 1 | 10% |
Unknown | 8 | 80% |
Demographic breakdown
Type | Count | As % |
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Scientists | 5 | 50% |
Members of the public | 5 | 50% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 117 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 37 | 32% |
Researcher | 17 | 15% |
Student > Master | 8 | 7% |
Student > Bachelor | 5 | 4% |
Unspecified | 4 | 3% |
Other | 15 | 13% |
Unknown | 31 | 26% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 49 | 42% |
Agricultural and Biological Sciences | 13 | 11% |
Medicine and Dentistry | 10 | 9% |
Unspecified | 4 | 3% |
Nursing and Health Professions | 3 | 3% |
Other | 6 | 5% |
Unknown | 32 | 27% |