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The bromodomain protein BRD4 regulates splicing during heat shock

ABSTRACT: During heat stress cyto-protective genes including heat shock proteins are transcriptionally up-regulated and post-transcriptional splicing is inhibited. In contrast, co-transcriptional mRNA-splicing is maintained. These factors closely resemble the proteotoxic stress response during tumor development. The bromodomain protein BRD4 has been identified as an integral member of the oxidative stress as well as of the inflammatory response. Furthermore, there is evidence for BRD4's role in splicing regulation; Using RNA-Seq analyses we indeed found a significant increase in splicing inhibition, in particular intron retentions, during heat treatment in BRD4-deficient cells, but not under normal conditions. Subsequent experiments revealed that heat stress leads to the recruitment of BRD4 to nuclear stress bodies, to the interaction with the heat shock factor 1 (HSF1) and to the transcriptional up-regulation of non-coding Sat III RNA transcripts. These findings implicate BRD4 as a central regulator of splicing during heat stress. Since BRD4 is a potent target for anti-cancer therapies, our data linking BRD4 to the splicing machinery and the heat stress response - give additional insight into the mode of action of BRD4 inhibitors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE73471 | GEO | 2016/09/07

SECONDARY ACCESSION(S): PRJNA297109

REPOSITORIES: GEO

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The bromodomain protein BRD4 regulates splicing during heat shock

Project description:During heat stress cyto-protective genes including heat shock proteins are transcriptionally up-regulated and post-transcriptional splicing is inhibited. In contrast, co-transcriptional mRNA-splicing is maintained. These factors closely resemble the proteotoxic stress response during tumor development. The bromodomain protein BRD4 has been identified as an integral member of the oxidative stress as well as of the inflammatory response. Furthermore, there is evidence for BRD4's role in splicing regulation; Using RNA-Seq analyses we indeed found a significant increase in splicing inhibition, in particular intron retentions, during heat treatment in BRD4-deficient cells, but not under normal conditions. Subsequent experiments revealed that heat stress leads to the recruitment of BRD4 to nuclear stress bodies, to the interaction with the heat shock factor 1 (HSF1) and to the transcriptional up-regulation of non-coding Sat III RNA transcripts. These findings implicate BRD4 as a central regulator of splicing during heat stress. Since BRD4 is a potent target for anti-cancer therapies, our data linking BRD4 to the splicing machinery and the heat stress response - give additional insight into the mode of action of BRD4 inhibitors. WI38 cells have been treated by heatshock and anti BRD4 siRNA and combination.

2016-09-07 | E-GEOD-73471 | biostudies-arrayexpress

Homo sapiens

Project description:The bromodomain protein BRD4 regulates splicing during heat shock

| PRJNA297109 | ENA

Long non-coding Satellite III RNAs link the heat shock response and cell proliferation

Project description:Genomes of complex organisms encode a wide variety of long non-coding RNAs (lncRNAs) that regulate gene expression. In human cells exposed to heat stress, transcription of lncRNAs is highly induced from Satellite III sequences located primarily within locus 9q12. Expression of Sat III transcripts is dependent on heat shock factor 1, the master regulator of the heat shock response. Sat III transcripts serve as the backbone of specific subnuclear structures called nuclear Stress Bodies, nSBs. Despite being known for two decades, the function of nSBs and Sat III transcripts is unknown, which prompted us to conduct RNA profiling in human cells where Sat III transcripts were either intact or downregulated. Comparison of these cells revealed that under stress conditions, Sat III transcripts are involved in regulating a plethora of genes, including such associated with cell growth and protein homeostasis. Our results show that the presence of Sat III transcripts has a repressive effect on cell proliferation. We propose a model in which the inducible expression of Sat III transcripts restrains cell proliferation, allowing the cell to assess whether to grow or undergo apoptosis, and thereby suggesting a function for these lncRNAs in cell fate decisions and in restoring protein homeostasis. Total RNA from HEK293T cells transfected with siRNA against Satellite III transcripts or scrambled siRNA and heat shocked 1 h at 42Â°C , or heat shocked 1 h at 42 Â°C followed by recovery for 6 h, or left untreated was compared.

2015-12-31 | E-GEOD-58439 | biostudies-arrayexpress

Nascent-protein ubiquitination is required for heat shock-induced gene downregulation in human cells.

Project description:Proteotoxic stress such as heat shock causes heat-shock factor (HSF)-dependent transcriptional upregulation of chaperones. Heat shock also leads to a rapid and reversible downregulation of many genes, a process we term stress-induced transcriptional attenuation (SITA). The mechanism underlying this conserved phenomenon is unknown. Here we report that enhanced recruitment of negative transcription elongation factors to gene promoters in human cell lines induces SITA. A chemical inhibitor screen showed that active translation and protein ubiquitination are required for the response. We further find that proteins translated during heat shock are subjected to ubiquitination and that p38 kinase signaling connects cytosolic translation with gene downregulation. Notably, brain samples of subjects with Huntington's disease also show transcriptional attenuation, which is recapitulated in cellular models of protein aggregation similar to heat shock. Thus our work identifies an HSF-independent mechanism that links nascent-protein ubiquitination to transcriptional downregulation during heat shock, with potential ramifications in neurodegenerative diseases.

2019-02-07 | GSE112379 | GEO

Long non-coding Satellite III RNAs link the heat shock response and cell proliferation

2015-12-31 | GSE58439 | GEO

SUMOYLATION AND PROTEOTOSASIS NETWORKS CONVERGE DURING HEAT SHOCK TO MINIMIZE AGGREGATION AND PROMOTE DEGRADATION OF NUCLEAR PROTEINS

Project description:The role of stress-induced increases in SUMO2/3 conjugation during the Heat Shock Response (HSR) has remained enigmatic. We investigated SUMO signal transduction at the proteomic and functional level during the HSR in the context of cells depleted of proteostasis network components via chronic Heat Shock Factor 1 inhibition versus cells with normal pro-teostasis networks. In the recovery phase post-heat shock, SUMO2/3 conjugation remained high for a prolonged time in cells lacking sufficient chaperones. Similar results were obtained upon inhibiting HSP90, indicating that increased chaperone activity during the HSR is critical for the recovery of SUMO2/3 levels post-heat shock. Proteasome inhibition during the re-covery phase likewise prolonged SUMO2/3 conjugation, indicating that stress-induced SU-MO2/3 targets are subsequently degraded by the ubiquitin-proteasome system. Functionally, we show that SUMOylation profoundly enhances solubility of target proteins upon heat shock in vitro. Collectively, our results implicate SUMO2/3 as a rapid response factor protecting the proteome from aggregation upon proteotoxic stress.

2019-03-25 | PXD010231 | Pride

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

Cohesin regulates alternative splicing alone or with BRD4

Project description:By targeted depletion of Cohesin (RAD21 subunit) or BRD4 alone or together, we have established that cohesin alone or with BRD4 regulates the alternative splicing of a large subset of genes under both physiological and heat shock conditions.

2022-08-31 | GSE182960 | GEO

HSF1-dependent and -independent regulation of the mammalian in vivo heat shock response and its impairment in Huntington’s disease

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

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

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