The bromodomain protein BRD4 regulates splicing during heat shock

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


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.

MeSH terms

  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Exons
  • HeLa Cells
  • Heat Shock Transcription Factors
  • Heat-Shock Response / genetics*
  • Histone Acetyltransferases
  • Histone Chaperones
  • Hot Temperature
  • Humans
  • Introns
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Protein Domains
  • RNA Splicing*
  • RNA, Messenger / genetics*
  • RNA, Messenger / metabolism
  • RNA, Untranslated / genetics*
  • RNA, Untranslated / metabolism
  • Sequence Analysis, RNA
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism


  • DNA-Binding Proteins
  • HSF1 protein, human
  • Heat Shock Transcription Factors
  • Histone Chaperones
  • Nuclear Proteins
  • RNA, Messenger
  • RNA, Untranslated
  • Transcription Factors
  • BRD1 protein, human
  • Histone Acetyltransferases