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| Status |
Public on Nov 26, 2016 |
| Title |
Deletion of Histone Deacetylase 3 in Adult Beta Cells Improves Glucose Tolerance via Increased Insulin Secretion |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
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.
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| 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)
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| Contributor(s) |
Remsberg JR, Lazar MA |
| Citation(s) |
28123935 |
| |
| Submission date |
Nov 25, 2016 |
| Last update date |
May 15, 2019 |
| Contact name |
Manashree Damle |
| E-mail(s) |
damle@molbio.mgh.harvard.edu
|
| Organization name |
Massachusetts General Hospital
|
| Department |
Molecular Biology
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| Lab |
Bob Kingston
|
| Street address |
185 Cambridge Street
|
| City |
Boston |
| State/province |
MA |
| ZIP/Postal code |
02155 |
| Country |
USA |
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| Platforms (1) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
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| Samples (26)
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| Relations |
| BioProject |
PRJNA354962 |
| SRA |
SRP093925 |
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