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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 8

PAX6 function in human β cells.

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PAX6 function in human β cells.
(A) Change in β cell gene expression fol...
(A) Change in β cell gene expression following PAX6 knockdown in human EndoC-βH2 cells. (B) Ghrelin+ cells in human islets did not express PAX6, as shown by costaining of human pancreatic sections for PAX6 (green), ghrelin (red), and insulin (blue). Material was from a 9-year-old healthy donor (obtained from nPOD). Original magnification, ×400. (C) PAX6-binding sites in FOXA2 and SLC2A2 (encoding GLUT2) enhancers (Enh) (enhancers are highlighted in rectangles; the distance from the transcription start site is indicated). Note the active enhancer histone marks as well as the binding of all other β cell TFs in the same genomic position. (D) Venn diagram showing the overlap of genes bound by PAX6 in murine and human β cells. Note the β cell–specific gene sets enriched in the common group (with P values of 1.58 × 10–21, 1.5 × 10–16, 6.05 × 10–14, 6.65 × 10–12, and 5.07 × 10–10, respectively). MODY, maturity-onset diabetes of the young; T2D, type 2 diabetes.
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