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
Mentions: Next, we compared the number of reads obtained in Insm1, Neurod1 or Foxa2 ChIP-seq experiments and observed that read numbers were highest at sites co-occupied by all three factors (Fig 6A). Comparison of the distribution of co-occupied and ‘Insm1 only’ sites in the genome demonstrated that co-occupied sites were depleted of promoter and enriched in intergenic and intronic sequences (Fig 6B). The co-recruitment of Insm1, Neurod1 and Foxa2 was also experimentally tested by ChIP-PCR in both SJ β-cells and murine islets. Indeed, all tested sites were enriched (Fig 6C and D). Thus, Insm1, Neurod1 and Foxa2 frequently bind in close proximity in chromatin of pancreatic β-cells, and high affinity binding sites are enriched in sites co-occupied by all three factors.
Affiliation: Developmental Biology, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany email@example.com firstname.lastname@example.org.