An HSF1-JMJD6-HSP feedback circuit promotes cell adaptation to proteotoxic stress [ChIP-Seq]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE270671 | GEO | 2024/07/18
REPOSITORIES: GEO
Similar Datasets
Project description:Heat Shock Factor 1 (HSF1) is best known as the master transcriptional regulator of the heat-shock response (HSR), a conserved adaptive mechanism critical for protein homeostasis (proteostasis). Combining a genome-wide RNAi library with an HSR reporter, we identified JMJD6 as an essential mediator of HSF1 activity. In follow-up studies, we found that JMJD6 is itself a non-canonical transcriptional target of HSF1 which acts as a critical regulator of proteostasis. In a positive feedback circuit, HSF1 binds and promotes JMJD6 expression, which in turn reduces HSP70 R469 monomethylation to disrupt HSP70-HSF1 repressive complexes resulting in enhanced HSF1 activation. Thus, JMJD6 is intricately wired into the proteostasis network where it plays a critical role for cellular adaptation to proteotoxic stress.
2024-07-18 | GSE270672 | GEO
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
Project description:How heat shock inducesthe 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 HSRin yeast. Under nonstress conditions, nucleoplasmic Sis1 promotes interaction between the chaperone Hsp70 and the transcription factor Hsf1to repress the HSR. Heat shock triggers Sis1 to localize to the nucleolar periphery and condense on the ER surface with the ribosome quality control complex. Sis1 recruits the proteasome to this spatial network.Through localization dynamics, Sis1 relaysthe condition of the proteome to Hsf1.Thus, the activation state of the HSR is built into spatial organization of the proteostasis network.
2021-03-24 | PXD019170 | Pride
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
Project description:The heat shock response (HSR) is a mechanism to cope with proteotoxic stress by inducing the expression of molecular chaperones and other heat shock response genes. The HSR is evolutionarily well conserved and has been widely studied in bacteria, cell lines and lower eukaryotic model organisms. However, mechanistic insights into the HSR in higher eukaryotes, in particular in mammals, are limited. We have developed an in vivo heat shock protocol to analyze the HSR in mice and dissected heat shock factor 1 (HSF1)-dependent and -independent pathways. Whilst the induction of proteostasis-related genes was dependent on HSF1, the regulation of circadian function related genes, indicating that the circadian clock oscillators have been reset, was independent of its presence. Furthermore, we demonstrate that the in vivo HSR is impaired in mouse models of Huntington’s disease but we were unable to corroborate the general repression of transcription after a heat shock found in lower eukaryotes.
2017-03-03 | GSE95602 | GEO
Project description:Protein homeostasis and cellular fitness in the presence of proteotoxic stress is promoted by heat shock factor 1 (HSF1), which controls basal and stress-induced expression of molecular chaperones and other targets. The major heat shock proteins Hsp70 and Hsp90 in turn participate in a negative feedback loop that ensures appropriate coordination of the heat shock response with environmental conditions. Features of this regulatory circuit in the budding yeast Saccharomyces cerevisiae have been recently defined, most notably regarding direct interaction between Hsf1 and the constitutively expressed Hsp70 Ssa1. We sought to further explore the complex nature of Ssa1/Hsf1 regulation. Ssa1 is found to interact independently with both the previously defined CE2 site in the Hsf1 carboxyl-terminal transcriptional activation domain as well as a novel site that we identify within the amino-terminal activation domain. Consistent with both sites bearing a recognition signature for Hsp70, we demonstrate that Ssa1 contacts Hsf1 using its substrate binding domain and abolishing either regulatory site results in loss of Ssa1 association. Removing Hsp70 regulation of Hsf1 results in global dysregulation of Hsf1 transcriptional activity, with synergistic effects when both sites are disrupted together on both gene expression and cellular fitness. Finally, we find that Hsp70 interacts with both transcriptional activation domains of Hsf1 in the related yeast Lachancea kluyveri, implying a conserved mechanism of regulation to promote cellular proteostasis.
2019-04-16 | GSE129832 | GEO
Project description:Heat shock factor 1 (HSF1) is well known for its role in the heat shock response (HSR), where it drives a transcriptional program comprising heat shock protein (HSP) genes, and in tumorigenesis, where it drives a program comprising HSPs and many non-canonical target genes that support malignancy. Here, we find that HSF2, an HSF1 paralog with no significant role in the HSR, physically and functionally interacts with HSF1 across diverse types of cancer. HSF1 and HSF2 have strikingly similar chromatin occupancy and regulate a common set of genes which include both HSPs and non-canonical transcriptional targets with roles critical in supporting malignancy. Loss of either HSF1 or HSF2 results in a dysregulated response to nutrient stresses in vitro and reduced tumor progression in cancer cell line xenografts. Taken together, these findings establish HSF2 as a critical cofactor of HSF1 in driving a cancer cell transcriptional program to support the anabolic malignant state.
2022-03-15 | GSE194098 | GEO
Project description:Background. The Heat Shock Response (HSR) is an evolutionarily conserved mechanism that helps cells adapt to environmental stresses. Heat Shock Factor 1 (HSF1) is a master HSR transcription factor that is long known to bind at promoters of its target HSP genes to rapidly activate their transcription. However, recent genome-wide studies revealed HSF1 binding at thousands of sites outside of heat-shock responsive gene promoters, implying a broader role of HSF1 in HSR. Results. We asked how the widespread HSF1 binding is established and to what extent it may be related to transcription activation. To answer these questions, we examined responses of two different human cancer cell lines to two stimuli that induce HSR, exposure to 42C and inorganic arsenic at the ambient temperature, by manually integrating ChIP-sequencing against HSF1, RNA Pol II, H3K4Me3 with nascent RNA- and ATAC-sequencing datasets in cells before and during HSR induced by these two stimuli. We show that widespread HSF1 binding is a temperature-agnostic hallmark of HSR whose genome-wide patterns combine cell type specificity with robustness to the nature of a stimulus and magnitude of activation. Mechanistically, HSR involves amplification of pre-existing low level HSF1 binding with few changes in accessible chromatin. HSF1 binding patterns show more stability than transcriptionally activated genes both between conditions and between cell lines. Conclusions. Comparing responses of distant cell lines to two HSR-inducing stimuli allowed us to define several features of HSR. Genome-wide HSF1 binding is a sensitive readout of HSR whose genome-wide patterns retain cell type identity across a broad dynamic range. The pre-existing genomic architecture is retained during HSR down to individual loci. Context-specific transcription involving common HSF1 binding favors a model of regulation by combinatory interplay of rigid transcription factor patterns.
2023-10-30 | GSE209685 | GEO
Project description:Background. The Heat Shock Response (HSR) is an evolutionarily conserved mechanism that helps cells adapt to environmental stresses. Heat Shock Factor 1 (HSF1) is a master HSR transcription factor that is long known to bind at promoters of its target HSP genes to rapidly activate their transcription. However, recent genome-wide studies revealed HSF1 binding at thousands of sites outside of heat-shock responsive gene promoters, implying a broader role of HSF1 in HSR. Results. We asked how the widespread HSF1 binding is established and to what extent it may be related to transcription activation. To answer these questions, we examined responses of two different human cancer cell lines to two stimuli that induce HSR, exposure to 42C and inorganic arsenic at the ambient temperature, by manually integrating ChIP-sequencing against HSF1, RNA Pol II, H3K4Me3 with nascent RNA- and ATAC-sequencing datasets in cells before and during HSR induced by these two stimuli. We show that widespread HSF1 binding is a temperature-agnostic hallmark of HSR whose genome-wide patterns combine cell type specificity with robustness to the nature of a stimulus and magnitude of activation. Mechanistically, HSR involves amplification of pre-existing low level HSF1 binding with few changes in accessible chromatin. HSF1 binding patterns show more stability than transcriptionally activated genes both between conditions and between cell lines. Conclusions. Comparing responses of distant cell lines to two HSR-inducing stimuli allowed us to define several features of HSR. Genome-wide HSF1 binding is a sensitive readout of HSR whose genome-wide patterns retain cell type identity across a broad dynamic range. The pre-existing genomic architecture is retained during HSR down to individual loci. Context-specific transcription involving common HSF1 binding favors a model of regulation by combinatory interplay of rigid transcription factor patterns.
2023-10-30 | GSE209675 | GEO
Project description:Background. The Heat Shock Response (HSR) is an evolutionarily conserved mechanism that helps cells adapt to environmental stresses. Heat Shock Factor 1 (HSF1) is a master HSR transcription factor that is long known to bind at promoters of its target HSP genes to rapidly activate their transcription. However, recent genome-wide studies revealed HSF1 binding at thousands of sites outside of heat-shock responsive gene promoters, implying a broader role of HSF1 in HSR. Results. We asked how the widespread HSF1 binding is established and to what extent it may be related to transcription activation. To answer these questions, we examined responses of two different human cancer cell lines to two stimuli that induce HSR, exposure to 42C and inorganic arsenic at the ambient temperature, by manually integrating ChIP-sequencing against HSF1, RNA Pol II, H3K4Me3 with nascent RNA- and ATAC-sequencing datasets in cells before and during HSR induced by these two stimuli. We show that widespread HSF1 binding is a temperature-agnostic hallmark of HSR whose genome-wide patterns combine cell type specificity with robustness to the nature of a stimulus and magnitude of activation. Mechanistically, HSR involves amplification of pre-existing low level HSF1 binding with few changes in accessible chromatin. HSF1 binding patterns show more stability than transcriptionally activated genes both between conditions and between cell lines. Conclusions. Comparing responses of distant cell lines to two HSR-inducing stimuli allowed us to define several features of HSR. Genome-wide HSF1 binding is a sensitive readout of HSR whose genome-wide patterns retain cell type identity across a broad dynamic range. The pre-existing genomic architecture is retained during HSR down to individual loci. Context-specific transcription involving common HSF1 binding favors a model of regulation by combinatory interplay of rigid transcription factor patterns.
2023-10-30 | GSE209667 | GEO