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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

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

2015-12-31 | GSE58439 | GEO

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

2015-02-20 | GSE57397 | GEO

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

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

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

Distinct cellular tools of mild hyperthermia-induced acquired stress tolerance in Chinese Hamster Ovary cells

Project description:Mild stress could help cells to survive more severe environmental or pathophysiological conditions. In the current study, we investigated the cellular mechanisms which contribute to the development of stress tolerance upon a prolonged (0-12h) fever-like (40 °C) or a moderate (42.5 °C) hyperthermia in mammalian CHO cells. Our results indicate that mild heat triggers a distinct, dose dependent remodeling of the cellular lipidome followed by the expression of heat shock proteins only at higher heat dosages. A significant elevation in the relative concentration of sat-urated membrane lipid species, specific lysophosphatidylinositol and sphingolipid species sug-gests prompt membrane microdomain reorganization and an overall membrane rigidification in response to the fluidizing heat in a time dependent manner. RNAseq experiments reveal that mild heat initiate endoplasmic reticulum stress-related signaling cascades resulting in lipid re-arrangement and ultimately in an elevated resistance against membrane fluidization by benzyl alcohol. To protect cells against lethal, protein denaturing high temperatures the classical heat shock protein response was required. The different layers of stress response elicited by different heat dosages highlights the capability of cells to utilize multiple tools to gain resistance against or to survive lethal stress conditions.

2022-05-18 | GSE199531 | 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. Whole RNA was extracted from 1 million HCT116 WT or FBXW7KO cells using the RNAeasy kit (Qiagen) according to the manufacturer’s protocol. Poly-A+ (magnetic oligodT-containing beads (Invitrogen)) or Ribominus RNA was used for library preparation. cDNA preparation and strand-specific library construction was performed using the dUTP method. Libraries were sequenced on the Illumina HiSeq 2000 using 50bp single-read method. Differential gene expression analysis was performed for each matched recovery versus heat-shock pairs, separately in each biological replicate and cell line (WT or KO). Two types of comparisons were tested: (a) WT recovery vs WT heat shock, (b) FBXW7 KO recovery vs heat shock.

2015-02-20 | E-GEOD-57397 | biostudies-arrayexpress

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