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BET inhibition disrupts transcription but retains enhancer-promoter contact

Author

Listed:
  • 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
    University of Copenhagen
    University of Copenhagen)

  • 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)

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.

Suggested Citation

  • 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 & Thoma, 2021. "BET inhibition disrupts transcription but retains enhancer-promoter contact," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20400-z
    DOI: 10.1038/s41467-020-20400-z
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    Cited by:

    1. Ryuichiro Nakato & Toyonori Sakata & Jiankang Wang & Luis Augusto Eijy Nagai & Yuya Nagaoka & Gina Miku Oba & Masashige Bando & Katsuhiko Shirahige, 2023. "Context-dependent perturbations in chromatin folding and the transcriptome by cohesin and related factors," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Irene Robles-Rebollo & Sergi Cuartero & Adria Canellas-Socias & Sarah Wells & Mohammad M. Karimi & Elisabetta Mereu & Alexandra G. Chivu & Holger Heyn & Chad Whilding & Dirk Dormann & Samuel Marguerat, 2022. "Cohesin couples transcriptional bursting probabilities of inducible enhancers and promoters," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    3. Nicholas T. Crump & Alastair L. Smith & Laura Godfrey & Ana M. Dopico-Fernandez & Nicholas Denny & Joe R. Harman & Joseph C. Hamley & Nicole E. Jackson & Catherine Chahrour & Simone Riva & Siobhan Ric, 2023. "MLL-AF4 cooperates with PAF1 and FACT to drive high-density enhancer interactions in leukemia," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    4. Tomas Zelenka & Antonios Klonizakis & Despina Tsoukatou & Dionysios-Alexandros Papamatheakis & Sören Franzenburg & Petros Tzerpos & Ioannis-Rafail Tzonevrakis & George Papadogkonas & Manouela Kapsetak, 2022. "The 3D enhancer network of the developing T cell genome is shaped by SATB1," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    5. Yanli Liu & Zhong Wu & Jin Zhou & Dinesh K. A. Ramadurai & Katelyn L. Mortenson & Estrella Aguilera-Jimenez & Yifei Yan & Xiaojun Yang & Alison M. Taylor & Katherine E. Varley & Jason Gertz & Peter S., 2021. "A predominant enhancer co-amplified with the SOX2 oncogene is necessary and sufficient for its expression in squamous cancer," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    6. Annkatrin Bressin & Olga Jasnovidova & Mirjam Arnold & Elisabeth Altendorfer & Filip Trajkovski & Thomas A. Kratz & Joanna E. Handzlik & Denes Hnisz & Andreas Mayer, 2023. "High-sensitive nascent transcript sequencing reveals BRD4-specific control of widespread enhancer and target gene transcription," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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