Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Expression array from SIRT6WT and SIRT6KO muscle

ABSTRACT: SIRT6 is a member of a highly conserved family of NAD+-dependent deacetylases with various roles in metabolism, stress resistance, and life span. SIRT6- deficient mice develop normally but succumb to a lethal hypoglycemia early in life; however, the mechanism underlying this hypoglycemia remained unclear. Here, we demonstrate that SIRT6 functions as a histone H3K9 deacetylase to control the expres- sion of multiple glycolytic genes. Specifically, SIRT6 appears to function as a corepressor of the transcrip- tion factor Hif1a, a critical regulator of nutrient stress responses. Consistent with this notion, SIRT6-defi- cient cells exhibit increased Hif1a activity and show increased glucose uptake with upregulation of glycolysis and diminished mitochondrial respiration. Our studies uncover a role for the chromatin factor SIRT6 as a master regulator of glucose homeostasis and may provide the basis for novel therapeutic approaches against metabolic diseases, such as diabetes and obesity. RNA was prepared from muscle of three SIRT6 wild type and KO mice, and hybridized onto an Affymetrix GeneChip Mouse Genome 430 2.0 Array.

ORGANISM(S): Mus musculus

SUBMITTER: Raul Mostoslavsky

PROVIDER: E-GEOD-67780 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha.

Zhong Lei L D'Urso Agustina A Toiber Debra D Sebastian Carlos C Henry Ryan E RE Vadysirisack Douangsone D DD Guimaraes Alexander A Marinelli Brett B Wikstrom Jakob D JD Nir Tomer T Clish Clary B CB Vaitheesvaran Bhavapriya B Iliopoulos Othon O Kurland Irwin I Dor Yuval Y Weissleder Ralph R Shirihai Orian S OS Ellisen Leif W LW Espinosa Joaquin M JM Mostoslavsky Raul R

Cell 20100101 2

SIRT6 is a member of a highly conserved family of NAD(+)-dependent deacetylases with various roles in metabolism, stress resistance, and life span. SIRT6-deficient mice develop normally but succumb to a lethal hypoglycemia early in life; however, the mechanism underlying this hypoglycemia remained unclear. Here, we demonstrate that SIRT6 functions as a histone H3K9 deacetylase to control the expression of multiple glycolytic genes. Specifically, SIRT6 appears to function as a corepressor of the ...[more]

PMID: 20141841

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Project description: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.

Dataset Information

Expression array from SIRT6WT and SIRT6KO muscle

Publications

The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha.

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