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Series GSE104161 Query DataSets for GSE104161
Status Public on Dec 21, 2017
Title Gene expression profiles of SIRT6-deficient pancreatic beta cells from Ngn3-Cre Sirt6 f/f and MIP1-CreERT Sirt6 f/f mice
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Purpose: The complete understanding of how genetic and epigenetic components control beta cell differentiation and function is key to the discovery of novel therapeutic approaches to prevent beta cell dysfunction and failure in the progression of type 2 diabetes. Our goal was to elucidate the role of histone deacetylase SIRT6 in beta-cell development and homeostasis.
Methods: The Sirt6 endocrine progenitor cell conditional knockout (EKO) and beta-cell-specific knockout (BKO) mice were generated using the Cre-loxP system. Mice were assayed for islet morphology, glucose tolerance, glucose-stimulated insulin secretion, and susceptibility to streptozotocin. Transcriptional regulatory functions of SIRT6 in primary islets were evaluated by RNA-seq analysis. RT-qPCR and immunoblot were used to verify and investigate the gene expression changes. Chromatin occupancies of SIRT6, H3K9Ac, H3K56Ac, and active RNA Polymerase II were evaluated by chromatin immunoprecipitation.
Results: Deletion of Sirt6 in pancreatic endocrine progenitor cells did not affect endocrine morphology, beta cell mass, or insulin production, but did result in glucose intolerance and defective glucose-stimulated insulin secretion in mice. Conditional deletion of Sirt6 in adult beta cells reproduced the insulin secretion defect. Loss of Sirt6 resulted in aberrant upregulation of TXNIP. SIRT6 deficiency led to increased accumulations of H3K9Ac, H3K56Ac, and active RNA polymerase II at the promoter region of Txnip. SIRT6-deficient beta cells exhibited a time-dependent increase of H3K9Ac, H3K56Ac, and TXNIP levels. Furthermore, beta-cell-specific SIRT6 deficient mice showed increased sensitivity to streptozotocin.
Conclusions: Our results reveal that SIRT6 suppresses Txnip expression in beta-cells via deacetylation of histone H3 and plays a critical role in maintaining beta-cell function and viability. Agents that preserve SIRT6 activity may be beneficial for preventing the progression of type 2 diabetes.
Overall design Profiles of pancreatic beta cells gene expression from 2-week post tamoxifen MIP1-CreERT Sirt6 f/f and 2-month-old Ngn3-Cre Sirt6 f/f male mice were generated by RNA-sequencing with duplicate using Illumina HiSeq 2000 and 3000. Samples from MIP-CreERT Sirt6 f/+, MIP-CreERT Sirt6 +/+, and Ngn3-Cre Sirt6 +/+, which did not show phenotype, were used as controls for BKO and EKO models, respectively, in the differential gene expression analysis.
Contributor(s) Qin K, Wang P
Citation(s) 29322219
Submission date Sep 22, 2017
Last update date May 15, 2019
Contact name KUNHUA QIN
Phone 2153603146
Organization name Children's Hospital of Philadelphia
Lab Gerd A Blobel
Street address 3615 Civic Center Blvd, 315H
City Philadelphia
State/province PA
ZIP/Postal code 19104
Country USA
Platforms (2)
GPL13112 Illumina HiSeq 2000 (Mus musculus)
GPL21493 Illumina HiSeq 3000 (Mus musculus)
Samples (8)
GSM2790929 BKO replicate1
GSM2790930 BKO replicate2
GSM2790931 EKO replicate1
BioProject PRJNA411837
SRA SRP118713

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MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE104161_All_Genes_ReadCount.txt.gz 311.7 Kb (ftp)(http) TXT
GSE104161_DEGs_identified_from_BKO_model.xlsx 21.9 Kb (ftp)(http) XLSX
GSE104161_DEGs_identified_from_EKO_model.xlsx 35.8 Kb (ftp)(http) XLSX
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