BET inhibition disrupts transcription but retains enhancer-promoter contact

Nicholas T. Crump, Erica Ballabio, Laura Godfrey, Ross Thorne, Emmanouela Repapi, Jon Kerry, Marta Tapia, Peng Hua, Christoffer Lagerholm, Panagis Filippakopoulos, James O. J. Davies and Thomas A. Milne ()
Additional contact information
Nicholas T. Crump: University of Oxford
Erica Ballabio: University of Oxford
Laura Godfrey: University of Oxford
Ross Thorne: University of Oxford
Emmanouela Repapi: University of Oxford
Jon Kerry: University of Oxford
Marta Tapia: University of Oxford
Peng Hua: University of Oxford
Christoffer Lagerholm: University of Oxford
Panagis Filippakopoulos: University of Oxford
James O. J. Davies: University of Oxford
Thomas A. Milne: University of Oxford

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract Enhancers are DNA sequences that enable complex temporal and tissue-specific regulation of genes in higher eukaryotes. Although it is not entirely clear how enhancer-promoter interactions can increase gene expression, this proximity has been observed in multiple systems at multiple loci and is thought to be essential for the maintenance of gene expression. Bromodomain and Extra-Terminal domain (BET) and Mediator proteins have been shown capable of forming phase condensates and are thought to be essential for super-enhancer function. Here, we show that targeting of cells with inhibitors of BET proteins or pharmacological degradation of BET protein Bromodomain-containing protein 4 (BRD4) has a strong impact on transcription but very little impact on enhancer-promoter interactions. Dissolving phase condensates reduces BRD4 and Mediator binding at enhancers and can also strongly affect gene transcription, without disrupting enhancer-promoter interactions. These results suggest that activation of transcription and maintenance of enhancer-promoter interactions are separable events. Our findings further indicate that enhancer-promoter interactions are not dependent on high levels of BRD4 and Mediator, and are likely maintained by a complex set of factors including additional activator complexes and, at some sites, CTCF and cohesin.

Date: 2021
References: Add references at CitEc
Citations: View citations in EconPapers (6)

Downloads: (external link)
https://www.nature.com/articles/s41467-020-20400-z Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20400-z

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-020-20400-z

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().