Insm1 cooperates with Neurod1 and Foxa2 to maintain mature pancreatic ?-cell function.

ABSTRACT: Key transcription factors control the gene expression program in mature pancreatic ?-cells, but their integration into regulatory networks is little understood. Here, we show that Insm1, Neurod1 and Foxa2 directly interact and together bind regulatory sequences in the genome of mature pancreatic ?-cells. We used Insm1 ablation in mature ?-cells in mice and found pronounced deficits in insulin secretion and gene expression. Insm1-dependent genes identified previously in developing ?-cells markedly differ from the ones identified in the adult. In particular, adult mutant ?-cells resemble immature ?-cells of newborn mice in gene expression and functional properties. We defined Insm1, Neurod1 and Foxa2 binding sites associated with genes deregulated in Insm1 mutant ?-cells. Remarkably, combinatorial binding of Insm1, Neurod1 and Foxa2 but not binding of Insm1 alone explained a significant fraction of gene expression changes. Human genomic sequences corresponding to the murine sites occupied by Insm1/Neurod1/Foxa2 were enriched in single nucleotide polymorphisms associated with glycolytic traits. Thus, our data explain part of the mechanisms by which ?-cells maintain maturity: Combinatorial Insm1/Neurod1/Foxa2 binding identifies regulatory sequences that maintain the mature gene expression program in ?-cells, and disruption of this network results in functional failure.

SUBMITTER: Jia S 

PROVIDER: S-EPMC4492000 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature