OR14-02 Circadian Regulation of Chromatin State Mediates Pancreatic Islet Incretin Response

The circadian clock is programmed by an autoregulatory transcription feedback loop present in brain and peripheral tissues that coordinates metabolism with nutritional state and the sleep-wake cycle. Epidemiologic and genetic studies indicate circadian disruption as a risk factor in the development of diabetes. We have demonstrated that conditional ablation of the β cell clock in adult life leads to hypoinsulinemic diabetes, and through mRNA-sequencing in mouse and human islets we revealed clock control of gene networks involved in insulin secretion, nutrient sensing, and exocytosis. A remaining question is: How does the core molecular clock modulate time-of-day dependent chromatin state to regulate pancreatic islet response to glucose and insulin secretagogues? Here we report that loss of the pancreatic β cell molecular clock results in closed chromatin at cAMP-responsive gene regulatory elements and dysregulated cAMP-dependent coregulator recruitment following cAMP agonism, consistent with a role for the molecular clock in mediating cell response to environmental stimuli. Further, tandem analyses of ATAC- and ChIP-sequencing in synchronized islets revealed dynamic chromatin accessibility across the 24-hour cycle at genes regulating insulin secretion and at genomic regions enriched for signal-inducible and circadian transcription factor motifs. Our genome-wide sequencing reveals a new role for the clock in global chromatin remodeling underlying the incretin response in pancreatic β cells.