Related Experiment Video

Updated: Jun 13, 2025

Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay
09:07

Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay

Published on: December 19, 2018

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Resistance of estrogen receptor function to BET bromodomain inhibition is mediated by transcriptional coactivator

Sicong Zhang1, Robert G Roeder2

  • 1Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY, USA. szhang06@rockefeller.edu.

Nature Structural & Molecular Biology
|September 9, 2024
PubMed

Insights

Bromodomain inhibition fails to repress estrogen receptor targets due to intrinsic mechanisms. Bromodomain-containing protein 4 (BRD4) activates oncogenes independently of its bromodomains, highlighting therapeutic potential.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Cancer Biology

Background:

  • Bromodomain and extraterminal domain (BET) proteins are epigenetic readers crucial for gene transcription.
  • BET proteins, particularly BRD4, are implicated in cancer development and are therapeutic targets.

Purpose of the Study:

  • To investigate the mechanism by which bromodomain inhibition fails to repress estrogen receptor-driven oncogenes.
  • To elucidate the role of bromodomain-independent functions of BRD4 in transcriptional regulation.

Main Methods:

  • Investigated the interaction of BRD4 with estrogen receptor binding sites.
  • Assessed the role of the Mediator complex in BRD4 enhancer occupancy.
  • Analyzed post-initiation RNA polymerase II (Pol II) associated factors and their interaction with BET proteins.

Main Results:

  • Bromodomain inhibition does not repress key oncogenic targets of estrogen receptor.
  • BRD4 activates transcription of oncogenes like MYC independently of its bromodomains.
  • BET proteins regulate transcription elongation by modulating Pol II interactions with elongation factors (SPT5, SPT6, PAF1) via bromodomain-independent mechanisms.

Conclusions:

  • BRD4 possesses critical bromodomain-independent functions in transcriptional activation.
  • These findings reveal novel therapeutic strategies targeting bromodomain-independent BET protein activities.

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