Glucocorticoid signaling in pancreatic islets modulates gene regulatory programs and genetic risk of type 2 diabetes

Glucocorticoids are key regulators of glucose homeostasis and pancreatic islet function, but the gene regulatory programs driving responses to glucocorticoid signaling in islets and the contribution of these programs to diabetes risk are unknown. In this study we used ATAC-seq and RNA-seq to map chromatin accessibility and gene expression from eleven primary human islet samples cultured in vitro with the glucocorticoid dexamethasone at multiple doses and durations. We identified thousands of accessible chromatin sites and genes with significant changes in activity in response to glucocorticoids. Chromatin sites up-regulated in glucocorticoid signaling were prominently enriched for glucocorticoid receptor binding sites and up-regulated genes were enriched for ion transport and lipid metabolism, whereas down-regulated chromatin sites and genes were enriched for inflammatory, stress response and proliferative processes. Genetic variants associated with glucose levels and T2D risk were enriched in glucocorticoid-responsive chromatin sites, including fine-mapped variants at 51 known signals. Among fine-mapped variants in glucocorticoid-responsive chromatin, a likely casual variant at the 2p21 locus had glucocorticoid-dependent allelic effects on beta cell enhancer activity and affected SIX2 and SIX3 expression. Our results provide a comprehensive map of islet regulatory programs in response to glucocorticoids through which we uncover a role for islet glucocorticoid signaling in mediating genetic risk of T2D.
Author summary Glucocorticoids regulate inflammation and metabolism and are widely used in the treatment of immune disorders, although prolonged exposure to glucocorticoids can lead to the development of diabetes. In this study we determined the response of primary pancreatic islets, which are central to the development of diabetes, to the glucocorticoid dexamethasone at multiple doses and durations. We observed widespread changes in pancreatic islets after glucocorticoid treatment at glucocorticoid receptor binding sites, as well as at key genes involved in islet function and processes related to steroid and lipid metabolism, ion channel activity, inflammation, and growth. Genetic variants affecting type 2 diabetes and glucose levels were located in sites affected by glucocorticoids at many genomic regions, and highlighted genes regulated by these sites through which glucocorticoid signaling may contribute directly to the development of diabetes. Together these results provide key insight into how glucocorticoid treatment affects pancreatic islet function and risk of diabetes.