PAX6 maintains β cell identity by repressing genes of alternative islet cell types
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
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
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Research Article Endocrinology Genetics

PAX6 maintains β cell identity by repressing genes of alternative islet cell types

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.

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

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Figure 4

Origins of ghrelin- and glucagon-expressing cells in βPAX6 mice.

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Origins of ghrelin- and glucagon-expressing cells in βPAX6 mice. (A) Gra...
(A) Gradual increase in the fraction of islet cells expressing ghrelin in βPAX6 mice compared with expression in controls (No Cre and No TM, as in Supplemental Figure 2). All mice were 3–4 months of age, 1 week after tamoxifen injection, except for mice in the “1 month” group, which were analyzed 1 month after tamoxifen administration (green bar). n = 3, 6, 3, and 2 mice per group, respectively. (B) Pax6-deleted β cells strongly expressed ghrelin, but not glucagon, as shown by costaining of YFP (green), insulin (blue), and ghrelin or glucagon (red). Islets shown were from βPAX6 mice 1 week or 6 months after tamoxifen injection. Original magnification, ×400.