Epigenetic basis of physiology and pathophysiology of glucocorticoids action on pancreatic beta cells - Abstract Glucocorticoids (GCs) are steroid hormones synthesized by the adrenal gland and are fundamental regulators of a diverse array of physiological functions, including inflammation, cardiac function, and glucose homeostasis. The function of GCs is mediated by the glucocorticoid receptor (GR), a ligand-induced nuclear hormone receptor that governs the expression of genes in a cell-type-specific manner. While the action of GCs on adipose tissue, muscle, and liver has been extensively studied, the specific function of GCs in beta cells is far less understood. Our research indicates that GCs directly act on beta cells to induce gene expression essential for their function, but the molecular details of this process remain largely elusive. Furthermore, GC secretion follows a distinct circadian rhythm. However, how circadian GR activity integrates with the endogenous circadian clock machinery within beta cells to fine-tune islet function is largely unknown. Finally, chronic high exposure to GCs can induce islet dysfunction, but the pathophysiology of chronic GC action on islets is not well defined. In this project, we will deploy a combination of transcriptional, epigenetic, multi-omic, and physiological assays to systematically delineate the role of GCs in islets. In Aim 1, we will investigate how GR induces chromatin remodeling to create a subset of de novo enhancers and regulates downstream beta cell-specific gene expression. In Aim 2, we will utilize multiple beta cell-specific knockout models to ascertain how GR regulates circadian islet function in healthy and circadian-disrupted mice. Lastly, in Aim 3, we will explore how chronic exposure to non-physiological GCs induces beta cell dedifferentiation and failure in mouse and human. Collectively, this study aims to establish a comprehensive model of GC/GR function in beta cells at chromatin, cellular, and physiological levels.
