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Nucleic Acids Res. 2017 Jan 9;45(1):382-394. doi: 10.1093/nar/gkw729. Epub 2016 Aug 17.

The bromodomain protein BRD4 regulates splicing during heat shock.

Author information

1
Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Ihnestr.63-73, 14195 Berlin, Germany.
2
Department of Biology, Chemistry and Pharmacy, Free University Berlin, 14195 Berlin, Germany.
3
Functional Epigenomics, CCG, Medical Faculty, University of Cologne, Weyertal 115b, 50931 Cologne, Germany.
4
Otto-Warburg Laboratory 'Neurodegenerative disorders', Max Planck Institute for Molecular Genetics, Ihnestr. 63-73, 14195 Berlin, Germany.
5
Sequencing Core Facility, Max Planck Institute for Molecular Genetics, Ihnestr. 63-73, 14195 Berlin, Germany.
6
Department of Anesthesiology and Intensive Care Medicine, Experimental Anesthesiology and Pain Research, University of Cologne, 50931 Cologne, Germany.
7
Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Ihnestr.63-73, 14195 Berlin, Germany mschweig@uni-koeln.de.

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.

PMID:
27536004
PMCID:
PMC5224492
DOI:
10.1093/nar/gkw729
[Indexed for MEDLINE]
Free PMC Article

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