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Cited by 123Genomics and Chromatin DynamicsProtein Degradation and InhibitorsChromatin Remodeling and Cancer

BET inhibition disrupts transcription but retains enhancer-promoter contact

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Crump, Nicholas T., Ballabio, Erica, Godfrey, Laura, Thorne, Ross, Repapi, Emmanouela, Kerry, Jon, Tapia, Marta, Hua, Peng +4 more·2021·Nature Communications
DOI 10.1038/s41467-020-20400-zPMC PMC7801379

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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.

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  • Degrading Mediator and BRD4 has shown that these proteins are critical for gene expression.

    “Recent experiments degrading Mediator and BRD4 have shown that these proteins are critical for gene expression [69].”

    From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [69]

    The Discussion (page unavailable) says BRD4 and Mediator play a key role in the transcription of many genes. The Introduction describes this paper’s use of a BRD4-degrading compound, but its experiments reduced Mediator binding rather than degrading Mediator; it mentions MED14 degradation only in a separate study of enhancer–promoter contact. Thus the gene-expression conclusion is supported, but the description of the experiments is not fully supported. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Removing BRD4 (and, consequently, Mediator) from chromatin using chemical inhibitors did not perturb the majority of enhancer-promoter contacts, despite major changes in transcription.

    “Nonetheless, removing BRD4 (and, consequently, Mediator) from chromatin using chemical inhibitors did not perturb the majority of enhancer–promoter contacts, despite major changes in transcription [69].”

    From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [69]

    The Introduction and Results report major transcriptional changes while enhancer–promoter contacts remained largely intact after BET inhibitor treatment. However, the Discussion says the drugs reduced BRD4 and Mediator binding but left detectable binding, so describing both proteins as removed from chromatin overstates the treatment’s effect. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Mediator and BRD4 co-localise at very high levels at super-enhancers, long stretches of sequences with gene regulatory activity that generally drive greater levels of gene expression than regular enhancers.

    “In particular, Mediator and BRD4 co-localise at very high levels at “super-enhancers” (SEs): long stretches of sequences with gene regulatory activity that generally drive greater levels of gene expression than regular enhancers [69–72].”

    From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [69]

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References 107 · Cited by 123

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Authors
Crump, N. T., Ballabio, E., Godfrey, L., Thorne, R., Repapi, E., Kerry, J., Tapia, M., Hua, P., Lagerholm, C., Filippakopoulos, P., Davies, J. O. J., & Milne, T. A.
Affiliations
  • University of Oxford (GB)
  • University of Copenhagen (DK)
Corresponding author
Milne, Thomas A.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2021-01-11
Volume
12
Issue
1
Pages
223-223
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-020-20400-z
PMC
PMC7801379
OpenAlex
W2990311636
Cited by
123
References
107
Citations by year
2026: 9 · 2025: 10 · 2024: 12 · 2023: 29 · 2022: 31 · 2021: 28 · 2020: 4
FWCI
8.55
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Spiral (Imperial College London) (submittedVersion, other-oa)
Funders
RCUK | Medical Research Council (MR/N010051/1, MC_UU_12009/6, MC_UU_00016/6)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords
enhancer-promoter interactions, BET proteins, BRD4, Mediator complex, BET inhibitors, super-enhancers, gene transcription, transcriptional activation, CTCF, cohesin, chromatin regulation
MeSH terms
CCCTC-Binding Factor, Cohesins, Chromatin, Chromosomal Proteins, Non-Histone, DNA-Binding Proteins, Enhancer Elements, Genetic, Glycols, Histones, Humans, Leukemia, Models, Genetic, Promoter Regions, Genetic, Protein Binding, Transcription, Genetic, Proto-Oncogene Proteins c-myc, Cell Cycle Proteins, Cell Line, Tumor, Carcinogenesis

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