SIRT6 Is a Key Regulator of Pancreatic β-Cell Survival and Function During Aging
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ABSTRACT:
PROVIDER: PRJNA1214259 | ENA |
REPOSITORIES: ENA
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Project description:SIRT6 has been implicated in anti-aging at the organismal level; however, its role in pancreatic beta cell aging is unclear. This study investigated the role of SIRT6 in pancreatic beta cell aging using conditional SIRT6 transgenic overexpression mice at 10 and 16 months of age. Our data show that SIRT6 has a strong protective function against aging-associated oxidative stress, DNA damage, and multiple forms of cell death.
2025-08-23 | GSE287696 | GEO
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:SIRT6 is a key regulator of mitochondrial function in the brain
| PRJNA912711 | ENA
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: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:Telomere length is important for the maintaining the individual health of a species. However, recent studies have indicated that the telomere length of somatic cells can be drastically decreased in the offspring receiving in vitro fertilization (IVF) therapy, however, the underlying molecular mechanism remains unknown. Sirt6 is a NAD+-dependent epigenetic regulator that has recently been found to play an important role in maintaining telomere stability. Here, we report for the first time that NAD+ levels are significantly lower in blastocysts cultured in vitro than that in blastocysts developed in vivo, leading to impaired Sirt6 function, further triggering telomere shortening of the inner cell mass and possibly affecting newborn offspring. This phenotype could be effectively mitigated by supplementation with NMN, a precursor of NAD+, during in vitro culture.While it could not be achieved in Sirt6 conditional knockout embryos. Our results reveal the mechanism by which in vitro culture induces telomere shortening in preimplantation embryos, providing a potential target for improving in vitro culture conditions.
2025-07-07 | GSE280684 | GEO
Project description:Brain-specific SIRT6-KO mice present increased DNA damage, learning impairments, and neurodegenerative phenotypes, placing SIRT6 as a key protein in preventing neurodegeneration. In the aging brain, SIRT6 levels/activity decline, which is accentuated in Alzheimer's patients. To understand SIRT6 roles in transcript pattern changes, we analyzed transcriptomes of young WT, old WT and young SIRT6-KO mice brains, and found changes in gene expression related to healthy and pathological aging. In addition, we traced these differences in human and mouse samples of Alzheimer's and Parkinson's diseases, healthy aging and calorie restriction (CR). Our results define four gene expression categories that change with age in a pathological or non-pathological manner, which are either reversed or not by CR. We found that each of these gene expression categories is associated with specific transcription factors, thus serving as potential candidates for their category-specific regulation. One of these candidates is YY1, which we found to act together with SIRT6 regulating specific processes. We thus argue that SIRT6 has a pivotal role in preventing age-related transcriptional changes in brains. Therefore, reduced SIRT6 activity may drive pathological age-related gene expression signatures in the brain.
2021-06-18 | GSE178432 | GEO
Project description:SIRT6, the sixth member of sirtuin family proteins, has been identified as a crucial regulator in multiple molecular pathways related to aging, including genome stability, DNA damage repair, telomere maintenance and inflammation. However, the exact roles of SIRT6 during mammalian oocyte meiosis have not yet fully clarified. Here, we investigated the critical events during porcine oocyte meiotic maturation with the treatment of SIRT6 specific inhibitor SIRT6-IN-1. We found that SIRT6 inhibition resulted in oocyte meiotic failure by displaying the poor expansion of cumulus cells and reduced rate of polar body extrusion. Meanwhile, the compromised spindle assembly, chromosome alignment and actin dynamics were also observed in SIRT6-inhibited oocytes. Moreover, inhibition of SIRT6 led to the defective cytoplasmic maturation by showing the abnormal distribution of cortical granules and their component ovastacin. Notably, we identified that expression of genes related to oocyte meiosis, oxidative phosphorylation and cellular senescence was remarkably altered in SIRT6-inhibited oocytes by transcriptome analysis, and validated that the meiotic defects caused by SIRT6 inhibition resulted from the excessive ROS-induced early apoptosis in oocytes. Taken together, our findings demonstrate that SIRT6 promotes the porcine oocyte meiotic maturation via maintaining the organelle dynamics.
2021-03-16 | GSE161068 | GEO