RNAs interact with BRD4 to promote enhanced chromatin engagement and transcription activation

Homa Rahnamoun, Jihoon Lee, Zhengxi Sun, Hanbin Lu, Kristen M. Ramsey, Elizabeth A. Komives, Shannon M. Lauberth

Research output: Contribution to journalArticlepeer-review

77 Scopus citations

Abstract

The bromodomain and extra-terminal motif (BET) protein BRD4 binds to acetylated histones at enhancers and promoters via its bromodomains (BDs) to regulate transcriptional elongation. In human colorectal cancer cells, we found that BRD4 was recruited to enhancers that were co-occupied by mutant p53 and supported the synthesis of enhancer-directed transcripts (eRNAs) in response to chronic immune signaling. BRD4 selectively associated with eRNAs that were produced from BRD4-bound enhancers. Using biochemical and biophysical methods, we found that BRD4 BDs function cooperatively as docking sites for eRNAs and that the BDs of BRD2, BRD3, BRDT, BRG1, and BRD7 directly interact with eRNAs. BRD4-eRNA interactions increased BRD4 binding to acetylated histones in vitro and augmented BRD4 enhancer recruitment and transcriptional cofactor activities. Our results suggest a mechanism by which eRNAs are directly involved in gene regulation by modulating enhancer interactions and transcriptional functions of BRD4.

Original languageEnglish (US)
Pages (from-to)687-697
Number of pages11
JournalNature Structural and Molecular Biology
Volume25
Issue number8
DOIs
StatePublished - Aug 1 2018
Externally publishedYes

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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