SIRT6 Is a Key Regulator of Pancreatic β-Cell Survival and Function During Aging
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE287696 | GEO | 2025/08/23
REPOSITORIES: GEO
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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.
2017-12-21 | GSE104161 | GEO
Project description:Sirtuins (Sirt) are a family of enzymes that modify chromatin and other proteins to affect gene activity. Loss of Sirt6 leads to a progeria-like phenotype in mice, but the target of SIRT6 action has been elusive. Here we show that Sirt6 binds to thousands of gene promoters in a stress-inducible fashion, guided by the stress-responsive transcription factor NF-κB. Chromatin profiling by ChIP-chip analysis of Sirt6 and NF-KB component RelA combined with expression array data of wildtype, Sirt6 knockout and Sirt6 RelA double knockout cells demonstrates that RelA recruits Sirt6 to NF-KB targets in response to TNF-a induction and that many of these targets are important for senescence and aging. comparison of wild type, Sirt6-/- and Sirt6-/- RelA-/- MEF cells
2011-05-11 | E-GEOD-28585 | biostudies-arrayexpress
Project description:Sirtuins (Sirt) are a family of enzymes that modify chromatin and other proteins to affect gene activity. Loss of Sirt6 leads to a progeria-like phenotype in mice, but the target of SIRT6 action has been elusive. Here we show that Sirt6 binds to thousands of gene promoters in a stress-inducible fashion, guided by the stress-responsive transcription factor NF-?B. Chromatin profiling by ChIP-chip analysis of Sirt6 and NF-KB component RelA combined with expression array data of wildtype, Sirt6 knockout and Sirt6 RelA double knockout cells demonstrates that RelA recruits Sirt6 to NF-KB targets in response to TNF-a induction and that many of these targets are important for senescence and aging. comparison of wild type, RelA -/- and Sirt6-/- MEF cells
2011-05-11 | E-GEOD-28638 | biostudies-arrayexpress
Project description:The SIRT6 deacetylase has been implicated in DNA repair, telomere maintenance, glucose and lipid metabolism and, importantly, it has critical roles in the brain ranging from its development to neurodegeneration. Here, we combined transcriptomics and metabolomics approaches to characterize the functions of SIRT6 in mouse brains. Unexpectedly, our analysis reveals that SIRT6 is a central regulator of mitochondrial activity in the brain. SIRT6 deficiency in the brain leads to mitochondrial deficiency with a global downregulation of mitochondria-related genes and pronounced changes in metabolite content. We suggest that SIRT6 affects mitochondrial functions through its interaction with the transcription factor YY1 that, together, regulate mitochondrial gene expression. Moreover, SIRT6 target genes include SIRT3 and SIRT4, which are significantly downregulated in SIRT6-deficient brains. Our results demonstrate that the lack of SIRT6 leads to decreased mitochondrial gene expression and metabolomic changes of TCA cycle byproducts, including increased ROS production, reduced mitochondrial number, and impaired membrane potential that can be partially rescued by restoring SIRT3 and 4 levels. Importantly, the changes we observed in SIRT6 deficient brains are also occurring in aging human brains and particularly in patients with Alzheimer's, Parkinson's, Huntington's, and Amyotrophic lateral sclerosis disease. Overall, our results suggest that the reduced levels of SIRT6 in the aging brain and neurodegeneration initiate mitochondrial dysfunction by altering gene expression, ROS production and mitochondrial decay.
2023-02-03 | GSE221077 | GEO
Project description:Sirtuins (Sirt) are a family of enzymes that modify chromatin and other proteins to affect gene activity. Loss of Sirt6 leads to a progeria-like phenotype in mice, but the target of SIRT6 action has been elusive. Here we show that Sirt6 binds to thousands of gene promoters in a stress-inducible fashion, guided by the stress-responsive transcription factor NF-κB. Chromatin profiling by ChIP-chip analysis of Sirt6 and NF-KB component RelA combined with expression array data of wildtype, Sirt6 knockout and Sirt6 RelA double knockout cells demonstrates that RelA recruits Sirt6 to NF-KB targets in response to TNF-a induction and that many of these targets are important for senescence and aging.
2011-05-11 | GSE28585 | GEO
Project description:Sirtuins (Sirt) are a family of enzymes that modify chromatin and other proteins to affect gene activity. Loss of Sirt6 leads to a progeria-like phenotype in mice, but the target of SIRT6 action has been elusive. Here we show that Sirt6 binds to thousands of gene promoters in a stress-inducible fashion, guided by the stress-responsive transcription factor NF-κB. Chromatin profiling by ChIP-chip analysis of Sirt6 and NF-KB component RelA combined with expression array data of wildtype, Sirt6 knockout and Sirt6 RelA double knockout cells demonstrates that RelA recruits Sirt6 to NF-KB targets in response to TNF-a induction and that many of these targets are important for senescence and aging.
2011-05-11 | GSE28638 | GEO
Project description:Aging leads to a gradual decline in physical activity and disrupted energy homeostasis. The NAD+-dependent SIRT6 deacylase regulates aging and metabolism through mechanisms that largely remain unknown. Here, we show that SIRT6 overexpression leads to a reduction in frailty and lifespan extension in both male and female B6 mice. A combination of physiological assays, in vivo multi-omics analyses and 13C lactate tracing identified an age-dependent decline in glucose homeostasis and hepatic gluconeogenesis (GNG) capacity in wild type mice. In contrast, aged SIRT6-transgenic mice preserve GNG capacity and glucose homeostasis through an improvement in the utilization of two major GNG precursors, lactate and glycerol. To mediate these changes, mechanistically, SIRT6 increases hepatic GNG gene expression, de novo NAD+ synthesis, and systemically enhances glycerol release from adipose tissue. These findings show that SIRT6 optimizes energy homeostasis in old age to delay frailty and preserve healthy aging.
2021-03-11 | PXD021447 | Pride
Project description:Pericentric heterochromatin silencing at mammalian centromeres is essential for mitotic fidelity and genomic stability. Defective pericentric silencing is observed in senescent cells, aging tissues, and mammalian tumors, but the underlying mechanisms and functional consequences of these defects are unclear. Here, we uncover a pivotal role of the human SIRT6 enzyme in pericentric transcriptional silencing, and this function protects against mitotic defects, genomic instability, and cellular senescence. At pericentric heterochromatin, SIRT6 promotes deacetylation of a new substrate, histone H3 lysine K18 (H3K18), and inactivation of SIRT6 in cells leads to H3K18 hyperacetylation and aberrant accumulation of pericentric transcripts. Strikingly, RNAi-depletion of these transcripts rescues the mitotic and senescence phenotypes of SIRT6-deficient cells. Together, our findings reveal a new function for SIRT6 and H3K18Ac regulation at heterochromatin, and demonstrate the pathogenic role of de-regulated pericentric transcription in aging- and cancer- related cellular dysfunction. H3K18ac, H3K9ac, H3K9me3, H3K56ac and Input ChIP-seq for U2OS cell
2016-04-04 | E-GEOD-69809 | biostudies-arrayexpress
Project description:Chromatin remodeling proteins are frequently dysregulated in human cancer, yet little is known about how they control tumorigenesis. Here, we uncover an epigenetic program mediated by the NAD+-dependent histone deacetylase Sirtuin 6 (SIRT6) that is critical for suppression of pancreatic ductal adenocarcinoma (PDAC), one of the most lethal malignancies. SIRT6 inactivation accelerates PDAC progression and metastasis via upregulation of Lin28b, a negative regulator of the let-7 microRNA. SIRT6 loss results in histone hyperacetylation at the Lin28b promoter, Myc recruitment, and pronounced induction of Lin28b and downstream let-7 target genes, HMGA2, IGF2BP1 and IGF2BP3. This epigenetic program defines a distinct subset representing 30-40% of human PDAC, characterized by poor prognosis and an exquisite dependence on Lin28b for tumor growth. Thus, we identify SIRT6 as an important PDAC tumor suppressor, and uncover the Lin28b pathway as a potential therapeutic target in a molecularlydefined PDAC subset. ChIP-Seq experiments to examine H3K56ac histone modifications in murine PDAC cells that are Sirt6 wild type (WT), Sirt6 knock-out (KO), and Sirt6 KO cells engineered to express Sirt6 WT (Sirt6 KO + Sirt6 WT Restored).
2016-04-01 | E-GEOD-79503 | biostudies-arrayexpress
Project description:To find the SIRT6 and SIRT7 binding proteins, we expressed V5-tagged SIRT6 and SIRT7 and pulled down this protein with anti-V5 agarose affinity gel. Sirtuins are a family of NAD-dependent deacetylases which deacetylate not only histones but also a wide range of target proteins. Sirtuins are conserved from yeast to mammal, and are known to regulate many processes such as cellular metabolism, apoptosis, cellular senescence, cell cycle, and organism-level aging. Among the members of sirtuins showing different subcellular localization, SIRT1, SIRT6 and SIRT7 are localized in nucleus. Whereas many functions and interacting proteins of SIRT1 have been studied, functions of SIRT6 and SIRT7 are not extensively revealed yet. Since it is important to understand the molecular function of SIRT6 and SIRT7, we here aimed to identify interacting proteins in mammalian cells.<br>Extra primary submitter: <a href="mailto:nglee@postech.ac.kr" target="_top">Namgyu Lee</a>, Department of Life Sciences, Pohang University of Science and Technology, Pohang, 790-784, Republic of Korea<br>Lab head: <a href="mailto:kchoi@postech.ac.kr" target="_top">Kwan Yong Choi</a>, Department of Life Sciences and Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, 790-784, Republ ic of Korea
2014-04-28 | PXD000159 | Pride