Dynamic regulation of murine RNA Polymerase III transcription during heat shock stress
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE282678 | GEO | 2025/03/04
REPOSITORIES: GEO
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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:Heat shock response (HSR) is critical for survival of organisms undergoing proteotoxic stress. Heat shock factor 1 (HSF1) is widely believed to be the master regulator of this response. Here, we examined the kinetics of the transcriptional response and HSF1 binding changes genome-wide after heat shock (HS) with high sensitivity and high spatial and temporal resolution using PRO-seq and ChIP-seq assays respectively in wild type and in hsf1-deletion mouse embryonic fibroblasts. The transcriptional response is rapid, dynamic, and extensive with activation of several hundred genes and repression of several thousands of genes. Although HSF1 is critically required for classical inducible Heat Shock Protein (HSP) genes, it is not required for the majority of gene activation. HSF1 acts mechanistically to promote RNA polymerase II (Pol II) release from the promoter-proximal pause, while recruitment and initiation of Pol II are predominantly HSF1-independent. Surprisingly, a major class of cytoskeleton genes is immediately (within 2.5 minutes) and transiently activated in an HSF1-independent manner. A second wave of regulation is characterized by robust activation or repression of new sets of genes. The broad repression of thousands of genes, a quarter of which are repressed immediately upon HS and the rest are repressed in the second wave of regulation, is mediated at the level of decreasing Pol II pause release and not at prior steps of Pol II recruitment or initiation. Notably, heat shock does not induce transcription of some previously defined HSP genes, and HSF2 â a homolog of HSF1 â does not compensate for the lack of HSF1. Together, these findings indicate that mammalian cells cope with stress by rapidly inducing pervasive and dramatic changes in transcription that are largely modulated at the step of pause release, and only a fraction of this regulation is HSF1-dependent. Examination of transcriptional regulation before and after heat shock in WT, HSF1-/-, and HSF1&2-/- MEFs
2016-03-01 | E-GEOD-71708 | biostudies-arrayexpress
Project description:Heat shock response (HSR) is critical for survival of organisms undergoing proteotoxic stress. Heat shock factor 1 (HSF1) is widely believed to be the master regulator of this response. Here, we examined the kinetics of the transcriptional response and HSF1 binding changes genome-wide after heat shock (HS) with high sensitivity and high spatial and temporal resolution using PRO-seq and ChIP-seq assays respectively in wild type and in hsf1-deletion mouse embryonic fibroblasts. The transcriptional response is rapid, dynamic, and extensive with activation of several hundred genes and repression of several thousands of genes. Although HSF1 is critically required for classical inducible Heat Shock Protein (HSP) genes, it is not required for the majority of gene activation. HSF1 acts mechanistically to promote RNA polymerase II (Pol II) release from the promoter-proximal pause, while recruitment and initiation of Pol II are predominantly HSF1-independent. Surprisingly, a major class of cytoskeleton genes is immediately (within 2.5 minutes) and transiently activated in an HSF1-independent manner. A second wave of regulation is characterized by robust activation or repression of new sets of genes. The broad repression of thousands of genes, a quarter of which are repressed immediately upon HS and the rest are repressed in the second wave of regulation, is mediated at the level of decreasing Pol II pause release and not at prior steps of Pol II recruitment or initiation. Notably, heat shock does not induce transcription of some previously defined HSP genes, and HSF2 – a homolog of HSF1 – does not compensate for the lack of HSF1. Together, these findings indicate that mammalian cells cope with stress by rapidly inducing pervasive and dramatic changes in transcription that are largely modulated at the step of pause release, and only a fraction of this regulation is HSF1-dependent.
2016-03-01 | GSE71708 | 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 | GSE209667 | 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: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:Ambient temperature is one of the most important environment factors that direct all organisms for morphogenesis, metabolisms and growth. Plants have evolved efficient mechanisms adapting temperature fluctuation such as heat stress response (HSR). Although transcriptional regulatory network of plant HSR has been established, little is known on the genome-wide transcriptional changes within first several minutes upon heat shock (HS). To precisely measure the very first wave of transcriptional response to HS, we investigated the nascent RNA and mature mRNA from plant leaf tissue exposure to 5-min HS treatment using global run-on sequencing (GRO-seq) and RNA sequencing (RNA-seq) methods. We found that only a small group of genes were both up- or down-regulated at nascent RNA and mRNA levels. Primed plants that already exposed to a mild heat stress induced a more drastic transcriptomic alteration than naïve plants which had not experienced a heat stress. Group A1 HEAT SHOCK TRANSCRIPTION FACTORs (HsfA1s) are the major transcription factors in charge of the very early transcriptional HSR. Within 5-minute HS, we also observed that: 1) Engaged RNA polymerase II (Pol II) was accumulated downstream of transcription start sites; 2) 5' pause-release is a rate limiting step for induction of some heat shock protein genes; 3) A good number of genes switched transcription modes; 4) Pervasive read-through was induced at terminators. Plants' HSR is transcriptionally very quick. GRO-seq is sensitive and robust to detect quick response to HS. Heat stress memory takes place at multiple steps of transcription cycles such as Pol II recruitment, 5' pausing, elongation and termination.
2020-07-11 | GSE128698 | GEO
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: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 | GSE270671 | GEO