title: 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.forename: Avital
authors.initials: A
authors.lastname: Swisa
authors.forename: Dana
authors.initials: D
authors.lastname: Avrahami
authors.forename: Noa
authors.initials: N
authors.lastname: Eden
authors.forename: Jia
authors.initials: J
authors.lastname: Zhang
authors.forename: Eseye
authors.initials: E
authors.lastname: Feleke
authors.forename: Tehila
authors.initials: T
authors.lastname: Dahan
authors.forename: Yamit
authors.initials: Y
authors.lastname: Cohen-Tayar
authors.forename: Miri
authors.initials: M
authors.lastname: Stolovich-Rain
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Kaestner
authors.forename: Benjamin
authors.initials: B
authors.lastname: Glaser
authors.forename: Ruth
authors.initials: R
authors.lastname: Ashery-Padan
authors.forename: Yuval
authors.initials: Y
authors.lastname: Dor
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016883:Diabetic Ketoacidosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004742:Enhancer Elements, Genetic; D017353:Gene Deletion; D005786:Gene Expression Regulation; D050416:Glucagon-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D000071841:PAX6 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; C000605732:Pax6 protein, mouse