<i>Insulin</i> promoter in human pancreatic β cells contacts diabetes susceptibility loci and regulates genes affecting insulin metabolism.

Abstract

Both type 1 and type 2 diabetes involve a complex interplay between genetic, epigenetic, and environmental factors. Our laboratory has been interested in the physical interactions, in nuclei of human pancreatic β cells, between the insulin (<i>INS)</i> gene and other genes that are involved in insulin metabolism. We have identified, using Circularized Chromosome Conformation Capture (4C), many physical contacts in a human pancreatic β cell line between the <i>INS</i> promoter on chromosome 11 and sites on most other chromosomes. Many of these contacts are associated with type 1 or type 2 diabetes susceptibility loci. To determine whether physical contact is correlated with an ability of the <i>INS</i> locus to affect expression of these genes, we knock down <i>INS</i> expression by targeting the promoter; 259 genes are either up or down-regulated. Of these, 46 make physical contact with <i>INS</i> We analyze a subset of the contacted genes and show that all are associated with acetylation of histone H3 lysine 27, a marker of actively expressed genes. To demonstrate the usefulness of this approach in revealing regulatory pathways, we identify from among the contacted sites the previously uncharacterized gene <i>SSTR5-AS1</i> and show that it plays an important role in controlling the effect of somatostatin-28 on insulin secretion. These results are consistent with models in which clustering of genes supports transcriptional activity. This may be a particularly important mechanism in pancreatic β cells and in other cells where a small subset of genes is expressed at high levels.