Universität zu Köln

Hussong, Michelle, Kaehler, Christian, Kerick, Martin ORCID: 0000-0002-6298-4514, Grimm, Christina ORCID: 0000-0002-4676-8870, Franz, Alexandra, Timmermann, Bernd, Welzel, Franziska, Isensee, Joerg ORCID: 0000-0002-3390-0051, Hucho, Tim ORCID: 0000-0002-4147-9308, Krobitsch, Sylvia and Schweiger, Michal R. (2017). The bromodomain protein BRD4 regulates splicing during heat shock. Nucleic Acids Res., 45 (1). S. 382 - 395. OXFORD: OXFORD UNIV PRESS. ISSN 1362-4962

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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 RNAsequencing 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 anticancer therapies.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hussong, Michelle UNSPECIFIED UNSPECIFIED UNSPECIFIED Kaehler, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Kerick, Martin UNSPECIFIED orcid.org/0000-0002-6298-4514 UNSPECIFIED Grimm, Christina UNSPECIFIED orcid.org/0000-0002-4676-8870 UNSPECIFIED Franz, Alexandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Timmermann, Bernd UNSPECIFIED UNSPECIFIED UNSPECIFIED Welzel, Franziska UNSPECIFIED UNSPECIFIED UNSPECIFIED Isensee, Joerg UNSPECIFIED orcid.org/0000-0002-3390-0051 UNSPECIFIED Hucho, Tim UNSPECIFIED orcid.org/0000-0002-4147-9308 UNSPECIFIED Krobitsch, Sylvia UNSPECIFIED UNSPECIFIED UNSPECIFIED Schweiger, Michal R. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-247142
DOI:	10.1093/nar/gkw729
Journal or Publication Title:	Nucleic Acids Res.
Volume:	45
Number:	1
Page Range:	S. 382 - 395
Date:	2017
Publisher:	OXFORD UNIV PRESS
Place of Publication:	OXFORD
ISSN:	1362-4962
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DIFFERENTIAL EXPRESSION ANALYSIS; WIDESPREAD INTRON RETENTION; NUCLEAR STRESS BODIES; GENE-EXPRESSION; HUMAN-CELLS; P-TEFB; TRANSCRIPTION; ELONGATION; MECHANISM; GRANULES Multiple languages Biochemistry & Molecular Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/24714