HSF-1 promotes longevity through ubiquilin-1 dependent mitochondrial remodelling
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ABSTRACT:
ORGANISM(S): Caenorhabditis elegans
PROVIDER: GSE241558 | GEO | 2023/09/01
REPOSITORIES: GEO
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Project description:Impaired protein homeostasis promotes age-associated tissue dysregulation, presenting a need for therapeutic approaches that can restore proteome integrity. The heat shock factor HSF-1 is the master transcriptional regulator of proteostasis and regulates the expression of heat shock proteins (HSPs), which facilitate proper protein folding, localisation, and degradation. Increased HSF-1 activity can suppress proteotoxicity and enhance longevity across species. Studies into the mechanisms behind these beneficial effects have mostly focused on HSPs; however, the precise mechanisms by which increased HSF-1 activity extends lifespan are not known. To address this, we conducted an RNAi screen for genes that promote longevity, in C. elegans over expressing HSF-1 (hsf-1 OE). We found that ubiquilin-1 (ubql-1), a multifaceted shuttle protein that functions in protein degradation pathways is necessary for full lifespan extension in hsf-1OE worms. Surprisingly, we find that lack of ubql-1 does not impact proteostasis capacity, but does alter mitochondrial dynamics, in hsf-1 OE worms. These effects are independent of mitophagy or the mitochondrial unfolded protein response (mitoUPR) suggesting enhanced turnover of mitochondrial outer membrane proteins may be important for increased longevity via the HSF-1-ubiquilin-1 axis. Additionally, we reveal a role for ubql-1, a protein quality control regulator in regulating lipid homeostasis in hsf-1 OE animals. Lack of ubql-1 in hsf-1 OE animals supresses the expression of a key mitochondrial β-oxidation and lipid mobilization gene regulated by NHR-49 - acyl-CoA synthetase-2, ACS-2 amongst other genes. We propose that ubql-1 is required for mito-fusion and metabolic modulations that promote longevity in hsf-1 OE by interacting with NHR-49.
2024-10-17 | PXD044595 | Pride
Project description:To determine the transcriptional program of HSF-1 in lifespan assurance in C. elegans, we coupled HSF-1 depletion specifically from the soma by auxin-inducible degron (AID) with RNA-seq analyses in whole animals. Depletion of HSF-1 from the soma was performed by transferring worms that express the E3 ligase TIR1 in somatic tissues and carry AID insertion to the endogenous HSF-1 onto NGM plates containing 1mM auxin (indole- 3-acetic acid, Sigma). The mock treatment was done by transferring worms to plates only containing the vehicle ethanol (EtOH). We analyzed the transcriptomic changes by RNA-seq upon soma-specific depletion of HSF-1 initiated at young adult stage for different length of time. We included the strains that only express TIR1 but do not have degron insertion at HSF-1 (CA1200) to control for the effects of auxin treatment and AID insertion into HSF-1. We performed analyses in the wild-type background (JTL611) as well as in the longlived, germline stem cell (GSC) arrested glp-1(e2141) mutant (JTL667). The AID model in fem-3(q20) mutant (JTL670) was included as a control for JTL667. JTL670 (fem-3) is sterile at 25°C as JTL667 (glp-1) but has normal lifespan.
2022-05-19 | GSE203087 | GEO
Project description:Purpose: We used RNA-Seq to compare the gene expression profiles in two long-lived C. elegans strains: (1) animals with a loss-of-function mutation in the hsb-1 gene, and (2) animals overexpressing hsf-1 under its endogenous promoter. Previous studies indicated that life span extension in both these strains is hsf-1-dependent. Methods: mRNA-Seq profiles for three biological replicates each of day 1 adult wild-type (N2 strain), hsb-1 mutant and hsf-1 overexpression strains were generated using 50 bp single-end sequencing on an Illumina HiSeq 2500 platform. The sequencing reads that passed quality control were aligned to the C. elegans reference transcriptome (WS220 release) using Bowtie 2 and splicing junctions were mapped using TopHat. Cufflinks was used to calculate FPKM values and CuffDiff 2 was used to identify differentially expressed genes based on the following two criteria: false discovery rate (FDR)-adjusted p value < 0.05 and fold-change ≥ 1.5. Results: Using our mRNA-Seq workflow, we mapped at least 14 million reads per sample to the C. elegans transcriptome at greater than 96 percent alignment rate for the raw reads. Expression of 7,478 genes was found to be significantly altered in the hsf-1 overexpression strain relative to wild-type worms, while only 1,855 genes had singnificantly different expression in the hsb-1 mutant strain relative to wild-type. Using our criterion of ≥ 1.5-fold change in gene expression, we found 1,820 and 662 genes to be differentially expressed relative to wild-type in hsf-1 overexpression and hsb-1 mutant strains, respectively. The 247 genes that were differentially expressed in both hsf-1 overexpression and hsb-1 mutant strains showed a strongly correlated expression pattern in the two strains. Conclusions: hsf-1 overexpression induces global transcriptional suppression in C. elegans. Genetic ablation of hsb-1 produces similar life span extension in worms as hsf-1 overexpression, but alters expression of a much smaller subset of the C. elegans transcriptome. Hence, HSB-1 is a specific regulator of the transactivation potential of HSF-1 that selectively modulates gene expression relevant to longevity determination in worms.
2019-05-29 | GSE119993 | GEO
Project description:To determine how gene expression changes in long-lived ash-2-deficient worms expressing the amyloidogenic Q40::YFP, and to assess how simultaneous depletion of hsf-1 effects these transcriptomic changes.
2023-10-16 | GSE227652 | GEO
Project description:To identify genes transcriptionally regulated by the nuclear hormone receptor, NHR-49, we performed RNA sequencing of wild-type and nhr-49(nr2041) loss-of-function mutant C. elegans. This transcriptomic dataset is utilized in the respective study to compare differentially regulated genes in nhr-49(nr2041) mutant worms to those treated with hsf-1 RNAi.
2022-08-30 | GSE199971 | GEO
Project description:Evaluating gene expression changes between wildtype worms, raga-1 mutants (loss of gene), and a neuronal rescue worm model
2019-08-27 | GSE132794 | GEO
Project description:To understand the roles of HSF-1 and its regulation in reproduction and heat shock response in a tissue-specific manner, we coupled tissue-specific HSF-1 depletion in C. elegans by auxin-inducible degron (AID) with genome-wide transcriptional analyses in whole animals. We used ChIP-seq to analyze the occupancy of HSF-1 (tagged with AID::GFP) and RNA Pol II in young adult (YA) animals grown at 20°C or upon heat shock (HS) at 34°C for 30 min following an acute depletion of HSF-1 by AID for 2 hours either in the somatic or in the germline cells. Depletion by AID was performed by transferring worms expressing the E3 ligase TIR1 and carrying AID insertion to endogenous HSF-1 (JTL611 or JTL621) to NGM plates containing 1mM auxin (indole- 3-acetic acid, Sigma). The mock treatment was done by transferring worms to plates only containing the vehicle ethanol (EtOH). In parallel, we used RNA-seq to analyze the heat shock respnse upon depletion of HSF-1 in the soma or the germline for 2 hours. In addition, we also analyzed the transcriptomic changes by RNA-seq upon tissue-specific depletion of HSF-1 initiated at young adult stage for different length of time. In all RNA-seq analyses, we included the strains that only express TIR1 but do not have degron insertion at HSF-1 (CA1200 and CA1199) to control for the effects of auxin treatment and AID insertion into HSF-1.
2021-07-01 | GSE162063 | GEO
Project description:To understand the roles of HSF-1 and its regulation in reproduction and heat shock response in a tissue-specific manner, we coupled tissue-specific HSF-1 depletion in C. elegans by auxin-inducible degron (AID) with genome-wide transcriptional analyses in whole animals. We used ChIP-seq to analyze the occupancy of HSF-1 (tagged with AID::GFP) and RNA Pol II in young adult (YA) animals grown at 20°C or upon heat shock (HS) at 34°C for 30 min following an acute depletion of HSF-1 by AID for 2 hours either in the somatic or in the germline cells. Depletion by AID was performed by transferring worms expressing the E3 ligase TIR1 and carrying AID insertion to endogenous HSF-1 (JTL611 or JTL621) to NGM plates containing 1mM auxin (indole- 3-acetic acid, Sigma). The mock treatment was done by transferring worms to plates only containing the vehicle ethanol (EtOH). In parallel, we used RNA-seq to analyze the heat shock respnse upon depletion of HSF-1 in the soma or the germline for 2 hours. In addition, we also analyzed the transcriptomic changes by RNA-seq upon tissue-specific depletion of HSF-1 initiated at young adult stage for different length of time. In all RNA-seq analyses, we included the strains that only express TIR1 but do not have degron insertion at HSF-1 (CA1200 and CA1199) to control for the effects of auxin treatment and AID insertion into HSF-1.
2021-07-01 | GSE162066 | GEO
Project description:To understand the roles of HSF-1 and its regulation in reproduction and heat shock response in a tissue-specific manner, we coupled tissue-specific HSF-1 depletion in C. elegans by auxin-inducible degron (AID) with genome-wide transcriptional analyses in whole animals. We used ChIP-seq to analyze the occupancy of HSF-1 (tagged with AID::GFP) and RNA Pol II in young adult (YA) animals grown at 20°C or upon heat shock (HS) at 34°C for 30 min following an acute depletion of HSF-1 by AID for 2 hours either in the somatic or in the germline cells. Depletion by AID was performed by transferring worms expressing the E3 ligase TIR1 and carrying AID insertion to endogenous HSF-1 (JTL611 or JTL621) to NGM plates containing 1mM auxin (indole- 3-acetic acid, Sigma). The mock treatment was done by transferring worms to plates only containing the vehicle ethanol (EtOH). In parallel, we used RNA-seq to analyze the heat shock respnse upon depletion of HSF-1 in the soma or the germline for 2 hours. In addition, we also analyzed the transcriptomic changes by RNA-seq upon tissue-specific depletion of HSF-1 initiated at young adult stage for different length of time. In all RNA-seq analyses, we included the strains that only express TIR1 but do not have degron insertion at HSF-1 (CA1200 and CA1199) to control for the effects of auxin treatment and AID insertion into HSF-1.
2021-07-01 | GSE162064 | GEO
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2021-10-01 | GSE168501 | GEO