Genomics

Dataset Information

167

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


ABSTRACT: 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 β-cell function, but a recent genetic study in mice has been contradictory. Here we address the functional role of HDAC3 in β-cells of adult mice. Methods: An HDAC3 β-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 β-cell specific knockout (HDAC3βKO) did not increase total pancreatic insulin content or β-cell mass. However, HDAC3βKO 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. Overall design: Genomic occupancy profiled by high throughput sequencing (ChIP-seq) from mouse islets for HDAC3 (3 control and 3 KO, and corresponding inputs); and transcriptome profiling through RNA-seq of control mouse islets and those lacking histone deacetylase 3 (two separate experiments, n=3 an n=5)

INSTRUMENT(S): Illumina HiSeq 2000 (Mus musculus)

SUBMITTER: Manashree Damle  

PROVIDER: GSE90531 | GEO | 2016-11-26

SECONDARY ACCESSION(S): PRJNA354962

REPOSITORIES: GEO

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Publications

Deletion of histone deacetylase 3 in adult beta cells improves glucose tolerance via increased insulin secretion.

Remsberg Jarrett R JR   Ediger Benjamin N BN   Ho Wesley Y WY   Damle Manashree M   Li Zhenghui Z   Teng Christopher C   Lanzillotta Cristina C   Stoffers Doris A DA   Lazar Mitchell A MA  

Molecular metabolism 20161122 1


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 β-cell function, but a recent genetic study in mice has been contradictory. Here we address the functional role of HDAC3 in β-cells of adult mice. METHODS:An HDAC3 β-cell specific  ...[more]

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