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PAX6 maintains β cell identity by repressing genes of alternative islet cell types
Avital Swisa, … , Ruth Ashery-Padan, Yuval Dor
Avital Swisa, … , Ruth Ashery-Padan, Yuval Dor
Published December 12, 2016
Citation Information: J Clin Invest. 2017;127(1):230-243. https://doi.org/10.1172/JCI88015.
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Research Article Endocrinology Genetics

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

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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 7

Regulation of insulin expression and processing by PAX6.

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Regulation of insulin expression and processing by PAX6.
(A) PC1/3 (enco...
(A) PC1/3 (encoded by Pcsk1) immunostaining was not reduced in Pax6-deleted β cells. Staining for PC1/3 (red), PAX6 (green), and insulin (blue) in cells from 3-month-old mice, 1 week after tamoxifen administration. Original magnification, ×400. (B) Pcsk1 mRNA level was not changed in sorted YFP+ β cells from βPAX6 mice, 1 week after tamoxifen administration. n = 4 control, 3 βPAX6 mice. (C) Proinsulin staining of βPAX6 and control pancreatic section showed no accumulation of proinsulin (red) in insulin– (blue) cells. Mice were littermates of those represented in A. Original magnification, ×400. (D) Transcriptional downregulation of insulin after Pax6 deletion. Reduced Ins1 mRNA, Ins1 pre-mRNA, Cre recombinase mRNA (driven by a transgenic insulin gene promoter), Pax6 mRNA, and Mafa mRNA after deletion of Pax6. Analysis was performed on sorted YFP+ cells from control (βYFP) and βPAX6 mice injected with tamoxifen at 1 month of age and sacrificed 1 or 3 weeks later. n = 3 for each group of mice. (E) ChIP with PAX6 antibody in Min6 cells showing enrichment for the Ins1 promoter (n = 2) compared with input. **P < 0.01 and ***P < 0.001, by 2-tailed Student’s t test.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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