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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 5

Transcriptomic analysis of PAX6-deficient β cells.

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Transcriptomic analysis of PAX6-deficient β cells.
(A) Gene set enrichme...
(A) Gene set enrichment analysis of sorted YFP+ cells from βPAX6 mice (n = 3) compared with YFP controls (n = 4), 1 week after tamoxifen injection. Genes that were previously shown to be upregulated in mouse β cell maturation (“Blum” adults vs. postnatal day 10 [ref. 76]; “Stolovich” postnatal day 35 vs. day 18 [Stolovich-Rain, unpublished observations]; see Supplemental Table 3) were downregulated in Pax6-deleted β cells, as were gene sets of insulin secretion and β cell proliferation. On the other hand, genes that were shown to be downregulated in maturation, as well as genes of nervous system development, were upregulated in Pax6-deleted β cells. Interestingly, gene sets associated with ion transport and microtubule and calcium channel activity were also upregulated. (B) Fold change in mRNA of specific islet cell genes. Ghrelin was the top upregulated gene in Pax6-deleted β cells. The FDR was below 0.05 for all genes, except Ins1 and Gcg (P < 0.05, FDR <0.15). (C) Enrichment analysis of differentially expressed genes obtained in KO models of other TFs essential in cells. Nkx6.1 deletion in β cells showed the closest similarity to Pax6 deletion.
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