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Key transcription factors control the gene expression program in mature pancreatic β‐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 β‐cells. We used  Insm1  ablation in mature β‐cells in mice and found pronounced deficits in insulin secretion and gene expression. Insm1‐dependent genes identified previously in developing β‐cells markedly differ from the ones identified in the adult. In particular, adult mutant β‐cells resemble immature β‐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 β‐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 β‐cells maintain maturity: Combinatorial Insm1/Neurod1/Foxa2 binding identifies regulatory sequences that maintain the mature gene expression program in β‐cells, and disruption of this network results in functional failure.

Insm1 cooperates with N eurod1 and F oxa2 to maintain mature pancreatic β‐cell function