SIRT7 regulates NUCKS1 chromatin binding to elicit metabolic and inflammatory gene expression in senescence and liver aging.
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ABSTRACT:
PROVIDER: PRJNA1256737 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR33369700_1.fastq.gz | Fastqsanger.gz | |||
| SRR33369700_2.fastq.gz | Fastqsanger.gz | |||
| SRR33369701_1.fastq.gz | Fastqsanger.gz | |||
| SRR33369701_2.fastq.gz | Fastqsanger.gz | |||
| SRR33369702_1.fastq.gz | Fastqsanger.gz |
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Project description:Sirtuins, a class of highly conserved histone/protein deacetylases, are heavily implicated in senescence and aging. The regulation of sirtuin proteins is tightly controlled both transcriptionally, translationally and via localization within the cell. While Sirtuin proteins are associated with aging, how their levels are regulated during aging across cell types and how they elicit tissue-specific age-related cellular changes are unclear. Here, we demonstrate that SIRT7 is targeted for degradation during senescence and liver aging. To uncover the significance and regulation of SIRT7 loss, we performed proteomics analysis and found that the E3 Ligase TRIP12 reduces SIRT7 levels during senescence. We identified the HMG box transcription factor NUCKS1 as a new SIRT7 interactor. We found that NUCKS1 is recruited onto chromatin during senescence, mediated by SIRT7 loss and accompanied by increased NUCKS1 acetylation. Depletion of NUCKS1 delayed senescence upon DNA damage leading to reduced inflammatory gene expression. Examination of transcriptional regulation by NUCKS1 during senescence revealed target genes of transcription factors NFKB1, RELA, and CEBP—all previously associated with senescence. Consistently, in Sirt7 KO mouse liver and in naturally aged livers, NUCKS1 was recruited to chromatin, bound at promoters and enhancers of age-related genes, including transcription factor Rela, and these bound sites had increased accessibility during aging. Overall, our results uncover NUCKS1 as a novel interactor of SIRT7, showing that proteosomal loss of SIRT7 during senescence and liver aging promotes chromatin binding of acetylated NUCKS1 to induce metabolic and inflammatory genes.
2025-06-01 | GSE295888 | GEO
Project description:Human mesenchymal stem cell (hMSC) senescence contributes to the imbalance of tissue homeostasis during aging. However, the connection between Sirtuin 7 (SIRT7) and hMSC homeostasis remains unclear. Here, we discovered a pivotal role of SIRT7 in protecting hMSC from senescence. We detected a decreased expression of SIRT7 during hMSC aging, while overexpression of which reversed premature hMSC senescence phenotypes. Mechanistically, we proved SIRT7 as a novel interacting protein of the heterochromatin complex, whose deficiency disrupted heterochromatin organization, thereby contributing to the derepression of the retrotransposon Long Interspersed Element 1 (LINE1 or L1). SIRT7-deficient hMSCs accumulated LINE1 in cytoplasm stimulating innate immune response by activated the cyclic GMP-AMP synthase (cGAS) and its downstream signaling effector stimulator of interferon genes (STING). Moreover, reverse-transcriptase inhibitors (RTis), such as Lamivudine (3TC), attenuated these senescence phenotypes of SIRT7-deficient hMSCs. Taken together, our findings identify SIRT7-heterochromatin via LINE1-cGAS/STING influence innate immune response, which contributes more comprehensive understanding of the physiological and function of SIRT7 and help us to find novel targets for the treatment of aging and aging relative diseases.
2020-06-29 | GSE146247 | GEO
Project description:SIRT7 is a member of the mammalian sirtuin family and functions as a NAD+-dependent deacylase. Studies in culture cells and human clinical data have implicated the role of SIRT7 in tumorigenesis. However, controversies were raised as to whether SIRT7 is oncogenic or tumor suppressive. Here we show that SIRT7 deficiency led to aneuploidy and aging-phenotypes, including senescence and nucleolin expansion. SIRT7 knockout mice were susceptible to DSS-induced colitis and alcohol-derived DNA damage, in advance led to intestinal epithelial barrier disruption. Devoid of SIRT7 aggravated the susceptibility of colorectal cancer incidence in APCMin/+ mouse model with further dysregulated Wnt signaling. Our findings indicated a tumor suppressive role of SIRT7 in vivo, novel strategies design for activating SIRT7 in treating colon cancer may be reappraised.
2020-09-16 | GSE138289 | GEO
Project description:Dysregulation of protein post-translational modification (PTM) can lead to a variety of pathological process, such as abnormal sperm development, malignant tumorigenesis, depression, and ageing process. SIRT7 is a NAD + dependent protein deacetylase. Besides known deacetylation, SIRT7 may also have the capacity to remove other acylation. However, the roles of SIRT7-induced other de-acylation in ageing is still largely unknown. Here, we found that the expression of SIRT7 was significantly increased in senescent fibroblasts and aged tissues. Knockdown or overexpression of SIRT7 can inhibit or promote fibroblast senescence. Knockdown of SIRT7 led to increased pan- lysine crotonylation (Kcr) levels in senescent fibroblasts. Using modern mass spectrometry (MS) technology, we identified 5149 Kcr sites across 1541 protein in senescent fibroblasts, providing the largest crotonylome dataset to date in senescent cells. Specifically, among the identified protein, we found SIRT7 de-crotonylated PHF5A, an alternative splicing factor, at K25. De-crotonylation of PHF5A K25 contributed to decreased CDK2 expression by Retained Intron (RI) induced abnormal alternative splicing, thereby accelerating fibroblasts senescence, supporting a key role of PHF5A K25 de-crotonylation in ageing. Collectively, our data revealed the molecular mechanism of SIRT7-induced k25 decrotonylation of PHF5A regulating aging, and provide new ideas and molecular targets for drug intervention in cellular ageing and the treatment of aging-related diseases, indicating that protein crotonylation has important implication in the regulation of ageing progress.
2022-02-17 | PXD027232 | Pride
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
Project description:SIRT7 counteracts mesenchymal stem cell senescence via stabilizing heterochromatin
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Project description:Sirtuins are key players in the response to oxidative, metabolic and genotoxic stress, and are involved in genome stability, metabolic homeostasis and aging. Originally described as NAD+-dependent deacetylases, some sirtuins are also characterized by poorly understood mono-ADP-ribosyltransferase (MADPRT) activity. Here we report that the deacetylase SirT7 is a dual sirtuin as it also features auto-MADPRT activity. Molecular and structural evidence suggests that this novel activity occurs at a second previously undefined active site that is physically separated in another domain. Specific abrogation of this activity alters SirT7 chromatin distribution, suggesting a role for this modification in SirT7 chromatin binding specificity and localization. Our studies uncover an epigenetic pathway by which ADP-ribosyl-SirT7 is recognized by the ADP-ribose reader macroH2A1.1, a histone variant involved in chromatin organization, metabolism and differentiation. Glucose starvation (GS) boosts this interaction and promotes SirT7 re-localization intergenic regions in a macroH2A1-dependent manner, which is required for specific up- or downregulation of a subset of nearby genes upon GS in primary cells and in vivo in the livers of calorie-restricted (CR) Wt and SirT7-/- mice. The level of expression of these genes decreases with age in SirT7-deficient mice, reinforcing the link between Sirtuins, CR and aging. Our work provides a novel perspective about sirtuin duality and suggests a key role for SirT7/macroH2A1.1 axis in mammalian glucose homeostasis, calorie restriction signaling and aging.
2019-08-07 | GSE128893 | GEO
Project description:Sirtuins are key players in the response to oxidative, metabolic and genotoxic stress, and are involved in genome stability, metabolic homeostasis and aging. Originally described as NAD+-dependent deacetylases, some sirtuins are also characterized by poorly understood mono-ADP-ribosyltransferase (MADPRT) activity. Here we report that the deacetylase SirT7 is a dual sirtuin as it also features auto-MADPRT activity. Molecular and structural evidence suggests that this novel activity occurs at a second previously undefined active site that is physically separated in another domain. Specific abrogation of this activity alters SirT7 chromatin distribution, suggesting a role for this modification in SirT7 chromatin binding specificity and localization. Our studies uncover an epigenetic pathway by which ADP-ribosyl-SirT7 is recognized by the ADP-ribose reader macroH2A1.1, a histone variant involved in chromatin organization, metabolism and differentiation. Glucose starvation (GS) boosts this interaction and promotes SirT7 re-localization intergenic regions in a macroH2A1-dependent manner, which is required for specific up- or downregulation of a subset of nearby genes upon GS in primary cells and in vivo in the livers of calorie-restricted (CR) Wt and SirT7-/- mice. The level of expression of these genes decreases with age in SirT7-deficient mice, reinforcing the link between Sirtuins, CR and aging. Our work provides a novel perspective about sirtuin duality and suggests a key role for SirT7/macroH2A1.1 axis in mammalian glucose homeostasis, calorie restriction signaling and aging.
2019-08-07 | GSE128487 | GEO
Project description:SIRT7 is a member of the mammalian sirtuin family of NAD+ dependent deacylases, and interacts with RNA polymerase I and UBF to regulate rDNA transcription. Various studies in mammalian cells and human clinical data have linked SIRT7 to cancer. However studies differ as to whether SIRT7 is oncogenic or tumor suppressive. Here we analyzed SIRT7 knockout mice and found SIRT7 deficiency caused sub-Mendelian birth numbers and a reduction in body size. Moreover, at 18 month of age, roughly 60 % of the SIRT7 knockout mice develop hepatocellular carcinoma (HCC), in many cases leading to suspected metastasis. Several HCC associated genes were up-regulated in livers of mice as young as 6 months of age, particularly targets of the proto-oncogene, c- MYC. Indeed SIRT7 interacts with MYC at endogenous protein levels and also represses MYC activity. Our findings thus show that SIRT7 acts as a tumor suppressor in vivo, and may suggest novel strategies to treat liver cancer. The mRNAs from 3 replicates of mouse Wildtype liver compared to 3 replicates of mouse liver lacking SIRT7
2014-08-20 | E-GEOD-50076 | biostudies-arrayexpress