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LARP7 ameliorates cellular senescence and aging-related atherosclerosis by allosterically enhancing SIRT1 deacetylase activity

ABSTRACT: LARP7 ameliorates cellular senescence and aging-related atherosclerosis by allosterically enhancing SIRT1 deacetylase activity

PROVIDER: PRJNA672873 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12921813_1.fastq.gz	Fastqsanger.gz
	SRR12921813_2.fastq.gz	Fastqsanger.gz
	SRR12921814_1.fastq.gz	Fastqsanger.gz
	SRR12921814_2.fastq.gz	Fastqsanger.gz
	SRR12921815_1.fastq.gz	Fastqsanger.gz

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LARP7 ameliorates cellular senescence and aging-related atherosclerosis by allosterically enhancing SIRT1 deacetylase activity

Project description:Cell senescence is a cell state characterized with permanent cell cycle arrest and elevated proinflammatory secretome and associated with pleiotropic essential physiopathological processes. The persistent DNA damage response (DDR) is the major stress leading to senescence, however the molecular mechanism underling remains elusive. Here, we identified the La Ribonucleoprotein 7 (LARP7), a 7SK RNA binding protein, as a novel SIRT1 deacetylase activator. It directly interacted with SIRT1 allosteric regulatory domain and enhanced its deacetylase activity. DDR-mediated ATM activation trigged the extracellular shuttling and downregulation of LARP7 that dampened the SIRT1 deacetylase activity and enhanced p53 and NFB (p65) transcriptional activity by augmenting their acetylation. As a consequence, activated p53 and NFB arrested cell growth and promoted SASP genes expression, and thereby accelerated the cellular senescence. Inducible deletion of LARP7 in wildtype mouse led to senescent cell accumulation and premature ageing. Furthermore, we identified that ATM-LARP7-SIRT1-p53/NFB senescent axis was active in the aortic senescence and atherogenesis. Genetic depletion of LARP7 aggravated the atherogenesis but conversely, inhibited ATM activation or restoring LARP7 expression with genetic manipulation alleviated the vascular aging and atherogenesis. Together, this study identifies LARP7 as a novel SIRT1 cellular activator and it’s-mediated ATM-LARP7-SIRT1-p53/NFB axis is attributed to DDR-mediated cellular senescence and aging-related pathologies.

2021-10-30 | GSE160279 | GEO

LARP7, a new ROS sensor, protects against heart failure by enhancing mitochondrial biogenesis

Project description:LARP7 controls the SIRT1 activity and homeostasis, which is essential for mitochondrial biogenesis, energy production and cardiac function. The deprivation of LARP7 resulted from the activation ATM pathway attenuates the mitochondrial function and biogenesis and leads to the cardiomyopathy and heart failure. Method: Heart morphology and functions were assessed by gross anatomy, serial echocardiography and histology on sections; Mitochondrial morphology and activity were evaluated by TEM and seahorse assays. The therapeutic potential of LARP7 in heart failure was evaluated in mouse myocardial infarction model either with AAV9 infection or pharmacological inhibitor.

2020-08-14 | GSE155898 | GEO

The NAD+-Dependent SIRT1 Deacetylase Translates a Metabolic Switch into Regulatory Epigenetics in Skeletal Muscle Stem Cells

Project description:Selective genetic ablation of the SIRT1 deacetylase domain in skeletal muscle results in increased H4K16 acetylation and deregulated activation of the myogenic program in satellite cells To establish the role of the deacetylase SIRT1 in skeletal muscle we examined the genome wide distribution of H4K16ac in quiescent (FI) and proliferating (Cul) satellite cells isolated from WT mice (C57Bl/6 background) and SIRT1mKO (generated via breeding of Pax7cre/+ knock-in mice with mice containing the floxed exon 4 SIRT1 allele). We also analyzed the distribution of SIRT1 in quiescent and proliferating FACS isolated WT satellite cells (two replicates). We generated the mRNA profiles (at least two replicate for each experiment) of FACS isolated quiescent, proliferating and differentiating (1 day in differentiation medium) satellite cells of WT mice and SIRT1mKO. The selective genetic ablation of the SIRT1 deacetylase domain in skeletal muscle results in increased H4K16 acetylation and deregulated activation of the myogenic program.

2015-01-30 | E-GEOD-64379 | biostudies-arrayexpress

The role of SIRT1 deacetylase in neuromuscular aging and amyotrophic lateral sclerosis

Project description:SIRT1 deacetylase functions in a variety of cells and tissues to mitigate age- and disease-induced damages. However, it remains unknown if SIRT1 also acts to prevent pathological changes that accrue in motor units, and specifically alpha-motor neurons, with advancing age and during the progression of amyotrophic lateral sclerosis (ALS). Here, we show that SIRT1 expression decreases in the spinal cord of wild type mice with advancing age. Using mouse models that overexpress or inactivate SIRT1 in motor neurons, we discovered that SIRT1 prevents age-related degeneration of motor neurons’ presynaptic sites at neuromuscular junctions (NMJs). We also found that increasing SIRT1 in motor neurons delays degeneration of presynaptic sites at NMJs and extends the lifespan of SOD1G93A mice. Thus, SIRT1 has a similar effect on aging and ALS-affected motor neurons, two conditions in which a remarkable number of transcripts are similarly altered in the spinal cord. These include genes involved in inflammatory and immune responses and genes with known function at synapses. These findings show that SIRT1 functions to mitigate pathological changes induced by aging and ALS, two conditions with a surprising degree of overlap in the spinal cord.

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The NAD+-Dependent SIRT1 Deacetylase Translates a Metabolic Switch into Regulatory Epigenetics in Skeletal Muscle Stem Cells

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Project description:The goal of this project is to investigate the role of SIRT1, the most conserved mammalian NAD+-dependent protein deacetylase, in the regulation of heart development. SIRT1 is important for heart development and functions. However, the underlying molecular mechanisms remain undefined. In this study, we analyzed the gene expression profiles in E18.5 WT and SIRT1 KO mouse hearts.

2021-08-23 | GSE86835 | GEO

RNA-Seq profiling of Sirt1 deficient mouse oocytes to investigate Sirt1 role in maternal-zygotic transition

Project description:Sirtuin-1 (Sirt1), a NAD+-dependent histone deacetylase, exhibits several properties of a versatile driver of maternal-zygotic transition, due to its epigenetic and non-epigenetic substrates. The study was aimed at the dynamics of Sirt1 in early embryos and the contribution to maternal-zygotic transition. A conditional Sirt1-deficient knock-out mouse model was used. Females were hormonally stimulated and used as oocyte donors. oocytes were parthenogenetically activated and Sirt1-/- two-cell embryos were used for transcriptomic analysis.

2024-07-06 | E-MTAB-13483 | biostudies-arrayexpress

Sirt1-microRNA profile

Project description:Sirt1, a NAD-dependent deacetylase, has been shown involved in many complex biological functions. We previously demonstrated that Sirt-1 gain of function is neuroprotective in a model of neurodegenenration. We recently found that Sirt1 loss of function (Sirt1Δ mouse) impairs learning, memory, and synaptic plasticity. We used microarray screening to identify potential miRNAs that may be regulated by Sirt1 and ivolved in learning and memory. Total RNA from the hippocampus of SIRT1Δ and control mice was extracted and used for microRNA expression level evaluation.

2010-06-24 | GSE22530 | GEO

Expression analysis upon SIRT1 knockdown in MCF-7 cells

Project description:SIRT1 is a nuclear NAD+-dependent protein deacetylase. Expression microarray analysis was used to study the effect of SIRT1 knockdown on gene expression in MCF-7 breast cancer cells.

2009-05-28 | GSE13459 | GEO

Sirt1-microRNA profile

Project description:Sirt1, a NAD-dependent deacetylase, has been shown involved in many complex biological functions. We previously demonstrated that Sirt-1 gain of function is neuroprotective in a model of neurodegenenration. We recently found that Sirt1 loss of function (Sirt1Î mouse) impairs learning, memory, and synaptic plasticity. We used microarray screening to identify potential miRNAs that may be regulated by Sirt1 and ivolved in learning and memory. Total RNA from the hippocampus of SIRT1Î and control mice was extracted and used for microRNA expression level evaluation. Two group experiment, in duplicates. Each sample is compared to a common reference sample, comprised of an equal mixture of all 4 experimental samples.

2010-07-29 | E-GEOD-22530 | biostudies-arrayexpress