PLX303323

GSE90531: Deletion of Histone Deacetylase 3 in Adult Beta Cells Improves Glucose Tolerance via Increased Insulin Secretion

• Organsim mouse
• Type RNASEQ
• Target gene
• Project ARCHS4

Objective: Histone deacetylases are epigenetic regulators known to control gene transcription in various tissues. A member of this family, histone deacetylase 3 (HDAC3), has been shown to regulate metabolic genes. Cell culture studies with HDAC-specific inhibitors and siRNA suggest that HDAC3 plays a role in pancreatic -cell function, but a recent genetic study in mice has been contradictory. Here we address the functional role of HDAC3 in -cells of adult mice. Methods: An HDAC3 -cell specific knockout was generated in adult MIP-CreERT transgenic mice using the Cre-loxP system. Induction of HDAC3 deletion was initiated at 8 weeks of age with administration of tamoxifen in corn oil (2 mg/day for 5 days). Mice were assayed for glucose tolerance, glucose-stimulated insulin secretion, and islet function 2 weeks after induction of the knockout. Transcriptional functions of HDAC3 were assessed by ChIP-seq as well as RNA-seq comparing control and -cell knockout islets. Results: HDAC3 -cell specific knockout (HDAC3KO) did not increase total pancreatic insulin content or -cell mass. However, HDAC3KO mice demonstrated markedly improved glucose tolerance. This improved glucose metabolism coincided with increased basal and glucose-stimulated insulin secretion in vivo as well as in isolated islets. Cistromic and transcriptomic analyses of pancreatic islets revealed that HDAC3 regulates multiple genes that contribute to glucose-stimulated insulin secretion. Conclusions: HDAC3 plays an important role in regulating insulin secretion in vivo and therapeutic intervention may improve glucose homeostasis. SOURCE: Manashree Damle (mdamle@mail.med.upenn.edu) - Mitch Lazar University of Pennsylvania