Insm1 cooperates with Neurod1 and Foxa2 to maintain mature pancreatic β-cell function.
Bottom Line: We defined Insm1, Neurod1 and Foxa2 binding sites associated with genes deregulated in Insm1 mutant β-cells.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.
Affiliation: Developmental Biology, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany email@example.com firstname.lastname@example.org.Show MeSH
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Mentions: We next tested systematically for changes in gene expression in coInsm1 mutant islets by microarray analysis (GSE54044), which revealed deregulated genes in mutant islets (P-value < 0.05; 1,232 genes with FC > 1.2 and < 0.8; 352 with FC > 1.4 and < 0.6). Similar numbers of genes were up- and down-regulated. To define affected cellular processes, we performed Gene Ontology (GO) term analysis of differentially expressed genes. Consistent with glucose intolerance, deregulated genes were associated with biological processes critical for β-cell function, such as regulation of insulin secretion, response to hormone and glucose stimulus, and glucose metabolism (Fig 4A; Supplementary Table S1). Comparison with Insm1-dependent genes identified previously in the developing pancreas (Gierl et al, 2006) revealed little overlap (61 overlapping genes, Pearson's coefficient 0.21, Supplementary Table S2). Thus, Insm1 controls distinct sets of genes in developing and mature β-cells.
Affiliation: Developmental Biology, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany email@example.com firstname.lastname@example.org.