title: The bromodomain protein BRD4 regulates splicing during heat shock.
abstract: The cellular response to heat stress is an ancient and evolutionarily highly conserved defence mechanism characterised by the transcriptional up-regulation of cyto-protective genes and a partial inhibition of splicing. These features 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, mainly due to its role in the transcriptional regulation process. In addition, there are also several lines of evidence implicating BRD4 in the splicing process. Using RNA-sequencing we found a significant increase in splicing inhibition, in particular intron retentions (IR), following heat treatment in BRD4-depleted cells. This leads to a decrease of mRNA abundancy of the affected transcripts, most likely due to premature termination codons. Subsequent experiments revealed that BRD4 interacts with the heat shock factor 1 (HSF1) such that under heat stress BRD4 is recruited to nuclear stress bodies and non-coding SatIII RNA transcripts are up-regulated. These findings implicate BRD4 as an important regulator of splicing during heat stress. Our data which links BRD4 to the stress induced splicing process may provide novel mechanisms of BRD4 inhibitors in regard to anti-cancer therapies.
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Ihnestr.63-73, 14195 Berlin, Germany.|Department of Biology, Chemistry and Pharmacy, Free University Berlin, 14195 Berlin, Germany.|Functional Epigenomics, CCG, Medical Faculty, University of Cologne, Weyertal 115b, 50931 Cologne, Germany.
authors.forename: Michelle
authors.initials: M
authors.lastname: Hussong
authors.affiliation: Department of Biology, Chemistry and Pharmacy, Free University Berlin, 14195 Berlin, Germany.|Otto-Warburg Laboratory 'Neurodegenerative disorders', Max Planck Institute for Molecular Genetics, Ihnestr. 63-73, 14195 Berlin, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kaehler
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Ihnestr.63-73, 14195 Berlin, Germany.|Functional Epigenomics, CCG, Medical Faculty, University of Cologne, Weyertal 115b, 50931 Cologne, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Kerick
authors.affiliation: Functional Epigenomics, CCG, Medical Faculty, University of Cologne, Weyertal 115b, 50931 Cologne, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Grimm
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Ihnestr.63-73, 14195 Berlin, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Franz
authors.affiliation: Sequencing Core Facility, Max Planck Institute for Molecular Genetics, Ihnestr. 63-73, 14195 Berlin, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Timmermann
authors.affiliation: Otto-Warburg Laboratory 'Neurodegenerative disorders', Max Planck Institute for Molecular Genetics, Ihnestr. 63-73, 14195 Berlin, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Welzel
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Experimental Anesthesiology and Pain Research, University of Cologne, 50931 Cologne, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Isensee
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Experimental Anesthesiology and Pain Research, University of Cologne, 50931 Cologne, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Hucho
authors.affiliation: Otto-Warburg Laboratory 'Neurodegenerative disorders', Max Planck Institute for Molecular Genetics, Ihnestr. 63-73, 14195 Berlin, Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Krobitsch
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Ihnestr.63-73, 14195 Berlin, Germany mschweig@uni-koeln.de.|Functional Epigenomics, CCG, Medical Faculty, University of Cologne, Weyertal 115b, 50931 Cologne, Germany.
authors.forename: Michal R
authors.initials: MR
authors.lastname: Schweiger
mesh_terms: D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D006367:HeLa Cells; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response / Q000235:genetics*; D051548:Histone Acetyltransferases; D056488:Histone Chaperones; D006358:Hot Temperature; D006801:Humans; D007438:Introns; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D000072417:Protein Domains; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D022661:RNA, Untranslated / Q000235:genetics* / Q000378:metabolism; D017423:Sequence Analysis, RNA; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000092468:Bromodomain Containing Proteins
chemical_list: D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; D051548:Histone Acetyltransferases; D056488:Histone Chaperones; D009687:Nuclear Proteins; D012333:RNA, Messenger; D022661:RNA, Untranslated; D014157:Transcription Factors; C000619706:HSF1 protein, human; C402649:BRD1 protein, human; D000092468:Bromodomain Containing Proteins