Defining the Essential Function of Yeast Hsf1 Reveals a Compact Transcriptional Program for Maintaining Eukaryotic Proteostasis
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PROVIDER: PRJNA428450 | ENA |
REPOSITORIES: ENA
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Project description:We used the conditional chemical genetics approach known as “anchor away” (AA) to rapidly inactivate the essential yeast transcription factor Hsf1. We coupled Hsf1-AA to RNA-seq and NET-seq to define the genes whose expression depends on Hsf1 and performed Hsf1-3xFLAG-V5 ChIP-seq to validate direct targets. We also carried out a number of other perturbations to yeast stress pathways to show that most of the gene expression changes during heat shock are Hsf1-independent but depend on PKA signaling and the Msn2/4 general stress transcription factors. Finally, we generated RNA-seq in mouse ES cells and MEFs in wild type and hsf1-/- cells to define HSF1 targets in murine cells.
2018-01-11 | GSE108736 | GEO
Project description:Maintaining proteostasis is key to resisting stress and to promoting healthy aging. Proteostasis is necessary to preserve stem cell function, but little is known about the mechanisms that regulate proteostasis during stress in stem cells, and whether disruptions in proteostasis contribute stem cell aging is largely unexplored. We determined that ex vivo cultured mouse and human hematopoietic stem cells (HSCs) rapidly increase protein synthesis. This challenge to HSC proteostasis was associated with nuclear accumulation of Hsf1, and deletion of Hsf1 impaired HSC maintenance ex vivo. Strikingly, supplementing cultures with small molecules that enhance Hsf1 activation partially suppressed protein synthesis, rebalanced proteostasis, and supported retention of HSC serial reconstituting activity. Although Hsf1 was dispensable for young adult HSCs in vivo, Hsf1 deficiency increased protein synthesis and impaired the reconstituting activity of middle-aged HSCs. Hsf1 thus promotes proteostasis and the regenerative activity of HSCs in response to culture stress and aging.
2021-07-11 | GSE179413 | GEO
Project description:Maintaining proteostasis is key to resisting stress and to promoting healthy aging. Proteostasis is necessary to preserve stem cell function, but little is known about the mechanisms that regulate proteostasis during stress in stem cells, and whether disruptions in proteostasis contribute stem cell aging is largely unexplored. We determined that ex vivo cultured mouse and human hematopoietic stem cells (HSCs) rapidly increase protein synthesis. This challenge to HSC proteostasis was associated with nuclear accumulation of Hsf1, and deletion of Hsf1 impaired HSC maintenance ex vivo. Strikingly, supplementing cultures with small molecules that enhance Hsf1 activation partially suppressed protein synthesis, rebalanced proteostasis, and supported retention of HSC serial reconstituting activity. Although Hsf1 was dispensable for young adult HSCs in vivo, Hsf1 deficiency increased protein synthesis and impaired the reconstituting activity of middle-aged HSCs. Hsf1 thus promotes proteostasis and the regenerative activity of HSCs in response to culture stress and aging.
2021-07-11 | GSE179412 | GEO
Project description: Not available
| S-EPMC4938784 | biostudies-literature
Project description:Host protein folding stress responses can play important roles in RNA virus replication and evolution. Intriguingly, prior work revealed a complicated interplay between the cytosolic proteostasis stress response, controlled by its master regulator heat shock factor 1 (HSF1) and human immunodeficiency virus-1 (HIV-1). We sought to isolate HSF1 transcription factor activity from proteostasis stress and elucidate the function of HSF1 in HIV-1 lifecycle in absence of cellular stress. We used chemical genetic, stress-independent control of HSF1 activity to establish whether and how HSF1 influences HIV-1 replication. Stress-independent HSF1 induction decreased both the total quantity and infectivity of HIV-1 virions. Moreover, HIV-1 was unable to escape HSF1-mediated restriction over the course of several serial passages. These results promote continued consideration of the heat shock response as a potential target for antiviral drugs.
2022-01-30 | GSE137591 | GEO
Project description:Heat Shock Factor 1 (Hsf1) in yeast drives the basal transcription of key proteostasis factors and its activity is induced as part of the core heat shock response. In this study we stringently test the role of Hsf1 under basal and stress conditions using a newly constructed hsf1∆ strain. To assess how cells mount transcriptional stress responses when Hsf1 is inactivated, we performed mRNA-sequencing (mRNA-seq) upon hear shock (HS) or treatment with azetidine-2-carboxylic acid (AzC).
2023-05-16 | GSE232311 | GEO
Project description:Upon heat shock, Hsf1 protein is extensively phosphorylated, however, this modification is inhibited by an hsf1-bal mutation. To get genome-wide effect of the hyperphosphorylation on Hsf1-regulated transcription, the heat-induced gene expression profiles in HSF1 and hsf1-bal cells were compared. Keywords: stress response
2005-09-27 | GSE3361 | GEO
Project description:Proteostasis collapse, the diminished ability to maintain protein homeostasis, has been established as a hallmark of nematode aging. However, whether proteostasis collapse occurs in humans has remained unclear. Here, we demonstrate that proteostasis decline is intrinsic to human senescence. Using transcriptome-wide characterization of gene expression, splicing, and translation, we found a significant deterioration in the transcriptional activation of the heat shock response in stressed senescent cells. Furthermore, phosphorylated HSF1 nuclear localization and distribution were impaired in senescence. Interestingly, alternative splicing regulation was also dampened. Surprisingly, we found a decoupling between different unfolded protein response (UPR) branches in stressed senescent cells. While young cells initiated UPR-related translational and transcriptional regulatory responses, senescent cells showed enhanced translational regulation and endoplasmic reticulum (ER) stress sensing; however, they were unable to trigger UPR-related transcriptional responses. This was accompanied by diminished ATF6 nuclear localization in stressed senescent cells. Finally, we found that proteasome function was impaired following heat stress in senescent cells, and did not recover upon return to normal temperature. Together, our data unraveled a deterioration in the ability to mount dynamic stress transcriptional programs upon human senescence with broad implications on proteostasis control and connected proteostasis decline to human aging.
2020-12-09 | GSE124609 | GEO
Project description:In Huntington's disease (HD), polyglutamine expansions in the huntingtin (Htt) protein cause subtle changes in cellular functions that, over-time, lead to neurodegeneration and death. Studies have indicated that activation of the heat shock response can reduce many of the effects of mutant Htt in disease models, suggesting that the heat shock response is impaired in the disease. To understand the basis for this impairment, we have used genome-wide chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-Seq) to examine the effects of mutant Htt on the master regulator of the heat shock response, HSF1. We find that, under normal conditions, HSF1 function is highly similar in cells carrying either wild-type or mutant Htt. However, polyQ-expanded Htt severely blunts the HSF1-mediated stress response. Surprisingly, we find that the HSF1 targets most affected upon stress are not directly associated with proteostasis, but with cytoskeletal binding, focal adhesion and GTPase activity. Our data raise the intriguing hypothesis that the accumulated damage from life-long impairment in these stress responses may contribute significantly to the etiology of Huntington's disease. Affymetrix MG430 2.0 expression levels of wild-type (STHdhQ7/Q7) and mutant (STHdhQ111/Q111) striatal cells under growth condition (33 C) and upon heat shock (42 C for six hours)
2012-06-18 | E-GEOD-38001 | biostudies-arrayexpress
Project description:How heat shock induces the heat shock response (HSR) - a gene expression program encoding chaperones and other protein homeostasis (proteostasis) factors - remains an unresolved question in eukaryotic cell biology. Here we show that subcellular localization of the conserved J-protein Sis1 is a key regulator of the HSR in yeast. Under nonstress conditions, nucleoplasmic Sis1 promotes interaction between the chaperone Hsp70 and the transcription factor Hsf1 to repress the HSR. Heat shock triggers Sis1 to localize to the periphery of the nucleolus and to condense on the ER surface. Sis1 recruits the proteasome to this spatial network along with disaggregases and the ribosome quality control complex. Through localization dynamics, Sis1 relays the condition of the proteome to Hsf1. We conclude that the activation state of the HSR is determined by the spatial organization of the proteostasis network.
2020-02-26 | GSE145936 | GEO