Transcriptomics,Genomics

Dataset Information

145

Gene expression profiles of SIRT6-deficient pancreatic beta cells from Ngn3-Cre Sirt6 f/f and MIP1-CreERT Sirt6 f/f mice


ABSTRACT: 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.

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

SUBMITTER: Kunhua Qin  

PROVIDER: GSE104161 | GEO | 2017-12-21

SECONDARY ACCESSION(S): PRJNA411837

REPOSITORIES: GEO

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Publications

SIRT6-mediated transcriptional suppression of Txnip is critical for pancreatic beta cell function and survival in mice.

Qin Kunhua K   Zhang Ning N   Zhang Zhao Z   Nipper Michael M   Zhu Zhenxin Z   Leighton Jake J   Xu Kexin K   Musi Nicolas N   Wang Pei P  

Diabetologia 20180110 4


AIMS/HYPOTHESIS:Better 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 sirtuin 6 (SIRT6) in beta cell development and homeostasis. METHODS:Sirt6 endocrine progenitor cell conditional knockout and beta cell-specific knockout mice were generated usin  ...[more]

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