BET inhibition disrupts transcription but retains enhancer-promoter contact
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BET inhibition disrupts transcription but retains enhancer-promoter contact. / Crump, Nicholas T.; Ballabio, Erica; Godfrey, Laura; Thorne, Ross; Repapi, Emmanouela; Kerry, Jon; Tapia, Marta; Hua, Peng; Lagerholm, Christoffer; Filippakopoulos, Panagis; Davies, James O.J.; Milne, Thomas A.
I: Nature Communications, Bind 12, Nr. 1, 223, 2021.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - BET inhibition disrupts transcription but retains enhancer-promoter contact
AU - Crump, Nicholas T.
AU - Ballabio, Erica
AU - Godfrey, Laura
AU - Thorne, Ross
AU - Repapi, Emmanouela
AU - Kerry, Jon
AU - Tapia, Marta
AU - Hua, Peng
AU - Lagerholm, Christoffer
AU - Filippakopoulos, Panagis
AU - Davies, James O.J.
AU - Milne, Thomas A.
N1 - Publisher Copyright: © 2021, The Author(s).
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-020-20400-z
DO - 10.1038/s41467-020-20400-z
M3 - Journal article
C2 - 33431820
AN - SCOPUS:85099211231
VL - 12
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 223
ER -
ID: 274061894