PAX6 maintains β cell identity by repressing genes of alternative islet cell types
Open Access
- 12 December 2016
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 127 (1), 230-243
- https://doi.org/10.1172/jci88015
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.Keywords
This publication has 76 references indexed in Scilit:
- Inactivation of specific β cell transcription factors in type 2 diabetesJCI Insight, 2013
- Metabolic manifestations of insulin deficiency do not occur without glucagon actionProceedings of the National Academy of Sciences of the United States of America, 2012
- Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeoverJCI Insight, 2012
- Integrative genomics viewerNature Biotechnology, 2011
- Islet β-Cell-Specific MafA Transcription Requires the 5′-Flanking Conserved Region 3 Control DomainMolecular and Cellular Biology, 2010
- Pax6 Is a Human Neuroectoderm Cell Fate DeterminantCell Stem Cell, 2010
- Simple Combinations of Lineage-Determining Transcription Factors Prime cis-Regulatory Elements Required for Macrophage and B Cell IdentitiesMolecular Cell, 2010
- Conversion of adult pancreatic α-cells to β-cells after extreme β-cell lossNature, 2010
- Pdx1 ( MODY4 ) regulates pancreatic beta cell susceptibility to ER stressProceedings of the National Academy of Sciences of the United States of America, 2009
- Sox9 coordinates a transcriptional network in pancreatic progenitor cellsProceedings of the National Academy of Sciences of the United States of America, 2007