Adaptation of the insulin secretory response to fluctuating insulin demand is critical for blood glucose homeostasis. We postulated that the epigenome could link changes in metabolic state with adaptive insulin secretion. Here we show that perturbations of nutrient state lead to extensive changes to H3K27 acetylation in pancreatic islets. Genomic sites of H3K27ac deposition acutely regulated by feeding were enriched for binding by the histone demethylase Lsd1, a candidate nutrient sensor known to respond to hormonal and metabolic stimuli. Conditional deletion of Lsd1 in mouse β-cells resulted in hypoglycemia and fasting hyperinsulinemia. Lsd1-deficient β-cells exhibited changes in H3K4me1 and H3K27ac deposition at Lsd1-bound sites. These changes at the chromatin level associated with aberrant expression of nutrient signaling and metabolic genes. We further show that Lsd1 controls feeding-stimulated transcription downstream of cAMP, which has been implicated in the control of β-cell metabolism. Accordingly, Lsd1-deficient β-cells failed to attenuate glucose metabolism in the fasted state, resulting in basal insulin hypersecretion. Further supporting a role for Lsd1 in adaptive insulin secretion, islets from hyperinsulinemic db/db mice exhibited increased H3K27ac and H3K4me1 levels at Lsd1-bound sites. Moreover, genomic sites bound by LSD1 in human islets were enriched for genetic variants associated with fasting glucose and type 2 diabetes in genome-wide association studies, suggesting a conserved role of LSD1 in the regulation of insulin secretion. Combined, our findings provide evidence that nutrient state modulates adaptive insulin secretion through Lsd1-dependent changes to the epigenome.
M. Wortham: None. F. Liu: None. J. Fleischman: None. M. Wallace: None. A.R. Harrington: None. J. Chiou: None. K. Gaulton: None. C. Metallo: Employee; Spouse/Partner; ICON plc. Research Support; Self; Gilead Sciences, Inc., Nimbus Therapeutics. M. Sander: None.
National Institutes of Health (R01DK068471); JDRF (3-PDF-2014-193-A-N)