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Polyglutamine expanded huntingtin dramatically alters the genome-wide binding of HSF1 (ChIP-Seq)

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE38000 | GEO | 2012/06/19

SECONDARY ACCESSION(S): PRJNA167041

REPOSITORIES: GEO

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Polyglutamine expanded huntingtin dramatically alters the genome-wide binding of HSF1 (mRNA)

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

Polyglutamine expanded huntingtin dramatically alters the genome-wide binding of HSF1 (mRNA)

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.

2012-06-19 | GSE38001 | GEO

Polyglutamine expanded huntingtin dramatically alters the genome-wide binding of HSF1 (ChIP-Seq)

Project description:In HuntingtonM-bM-^@M-^Ys 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. ChIP-Seq experiments for HSF-1 were performed in striatal cells that express either wild-type or mutant Htt using ChIP-Seq technology under normal (33M-BM-0C) and heat shock (42M-BM-0C for six hours) conditions. The cells were crosslinked with 1% formaldehyde and immunoprecipitated using antibody sc-9144 (Santa Cruz Biotech) for HSF-1. Sequencing was performed using the Illumina Genome Analyzer II.

2012-06-19 | E-GEOD-38000 | biostudies-arrayexpress

Sivery2016 - A mammalian heat shock response model

Project description:Environmental stress, such as oxidative or heat stress, induces the activation of the heat shock response (HSR) and leads to an increase in the heat shock proteins (HSPs) level. These HSPs act as molecular chaperones to maintain cellular proteostasis. Controlled by highly intricate regulatory mechanisms, having stress-induced activation and feedback regulations with multiple partners, the HSR is still incompletely understood. In this context, we propose a minimal molecular model for the gene regulatory network of the HSR that reproduces quantitatively different heat shock experiments both on heat shock factor 1 (HSF1) and HSPs activities. This model, which is based on chemical kinetics laws, is kept with a low dimensionality without altering the biological interpretation of the model dynamics. This simplistic model highlights the titration of HSF1 by chaperones as the guiding line of the network. Moreover, by a steady states analysis of the network, three different temperature stress regimes appear: normal, acute, and chronic, where normal stress corresponds to pseudo thermal adaption. The protein triage that governs the fate of damaged proteins or the different stress regimes are consequences of the titration mechanism. The simplicity of the present model is of interest in order to study detailed modelling of cross regulation between the HSR and other major genetic networks like the cell cycle or the circadian clock. Sivéry, A., Courtade, E., Thommen, Q. (2016). A minimal titration model of the mammalian dynamical heat shock response. Physical biology, 13(6), 066008.

2022-01-25 | MODEL2201210001 | BioModels

Transriptional profiling upon heat shock and recovery in cells deficient for FBXW7 and their wild type counterpart.

Project description:FBXW7 modulates stress response by post-translational modification of HSF1 HSF1 orchestrates the heat-shock response upon exposure to heat stress and activates a transcriptional program vital for cancer cells. Genes positively regulated by HSF1 show increeased expression during heat shock while their expression is reduced during recovery. Genes negatively regulated by HSF1 show the opposite pattern. In this study we utilized the HCT116 FBXW7 KO colon cell line and its wild type counterpart to monitor gene expression changes during heat shock (42oC, 1 hour) and recovery (37oC for 2 hours post heat shock) using RNA sequencing. These results revealed that the heat-shock response pathway is prolonged in cells deficient for FBXW7.

2015-02-20 | GSE57397 | GEO

HSF1 mediated Gene regulation in T cells at normal (37C) and febrile (40C) temperatures

Project description:HSF1 is a major transcriptional regulator of heat shock responses. Many cells activate HSF1 in response to heat shock temperatures (>42oC) and other cellular stress causing agents. Unlike other cell types, T cells activate HSF1 in response to T cell activation or when exposed to febrile (40oC) temperatures, suggesting a role for HSF1 beyond the heat-shock response. We used microarray analysis and HSF1 knock-out mice to study the HSF1 mediated gene regulation in activated T cells under normal and fever temperatures.

2012-09-20 | GSE41005 | GEO

Genome-wide characterization of HSF1 binding in human WT and FBXW7 KO colon cancer cells under basal conditions and upon heat shock

Project description:FBXW7 modulates stress response by post-translational modification of HSF1 HSF1 orchestrates the heat-shock response upon exposure to heat stress and activates a transcriptional program vital for cancer cells. In this study we assayed for genome-wide localization of HSF1 enrichment in the HCT116 FBXW7 KO colon cells and their wild type counterpart in untreated cells and upon heat shock. These results revealed that accumulation of nuclear HSF1 in FBXW7 KO cells results in rewiring of the HSF1 transcriptional program.

2015-02-20 | GSE57398 | GEO

Simultaneous activation of heat shock and oxidative stress pathways by celastrol

Project description:Stress response pathways allow cells to rapidly sense and respond to deleterious environmental changes, including those caused by pathophysiological disease states. A previous screen for small molecules capable of activating the human heat shock response identified the triterpenoid celastrol as a potent activator of the heat shock transcription factor HSF1. We show here that celastrol likewise activates the homologous Hsf1 of Saccharomyces cerevisiae. Celastrol induced Hsf1 hyperphosphorylation and concurrently activated a synthetic transcriptional reporter as well as endogenous inducible Hsp70 proteins at the same effective concentration seen in mammalian cells. Moreover, celastrol treatment conferred significant resistance to subsequent lethal heat shock. Transcriptional profiling experiments revealed that in addition to Hsf1, celastrol treatment induced the Yap1-dependent oxidant defense regulon. Oxidative stress-responsive genes were likewise induced in mammalian cells, demonstrating that celastrol simultaneously activates two major cellular stress-mediating pathways. As the induction of cellular stress pathways has implications in the treatment of a variety of human diseases including neurodegenerative diosorders, cardiovascular disease and cancer, celastrol thus represents an attractive therapeutic compound. Keywords: single-dose, single time-point gene induction by natural small molecule celastrol compared to heat shock in wild type (BY4741) Saccahromyces cerevisiae

2006-08-26 | GSE5608 | GEO

Genetic inactivation of essential HSF1 reveals an isolated transcriptional stress response selectively induced by protein misfolding

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

Genome-wide characterization of HSF1 binding in human WT and FBXW7 KO colon cancer cells under basal conditions and upon heat shock

Project description:FBXW7 modulates stress response by post-translational modification of HSF1 HSF1 orchestrates the heat-shock response upon exposure to heat stress and activates a transcriptional program vital for cancer cells. In this study we assayed for genome-wide localization of HSF1 enrichment in the HCT116 FBXW7 KO colon cells and their wild type counterpart in untreated cells and upon heat shock. These results revealed that accumulation of nuclear HSF1 in FBXW7 KO cells results in rewiring of the HSF1 transcriptional program. Five million cells were used for the ChIP and precipitated using 5 micrograms of antibody (cell signaling, 4356) against human HSF1

2015-02-20 | E-GEOD-57398 | biostudies-arrayexpress

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