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BET bromodomain proteins regulate enhancer function during adipogenesis.

Jonathan D Brown1, Zachary B Feldman2, Sean P Doherty2

  • 1Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN 37232; jonathan.d.brown@vanderbilt.edu jplutzky@bwh.harvard.edu james.bradner@novartis.com.

Proceedings of the National Academy of Sciences of the United States of America
|February 16, 2018
PubMed
Summary
This summary is machine-generated.

BRD4, a bromodomain-containing protein, regulates adipogenesis by controlling PPARγ and C/EBPα expression. Inhibition of BET proteins blocks adipogenesis by disrupting BRD4 binding to enhancers.

Keywords:
BET bromodomainadipogenesischromatincoactivatortranscription

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Area of Science:

  • Molecular Biology
  • Cell Biology
  • Epigenetics

Background:

  • Developmental transitions rely on master regulatory transcription factors.
  • PPARγ and C/EBPα are key transcription factors in adipogenesis.
  • Coactivators of PPARγ and C/EBPα are not fully understood.

Purpose of the Study:

  • To investigate the role of BRD4 in regulating PPARγ and C/EBPα expression.
  • To identify coactivators involved in the adipocyte cell state transition.
  • To elucidate the function of de novo super-enhancers in adipogenesis.

Main Methods:

  • Chromatin occupancy analysis of BRD4 during adipogenesis in 3T3L1 fibroblasts.
  • Inhibition of BET bromodomain proteins to assess effects on adipogenesis.
  • CRISPR interference (CRISPRi) to silence regulatory elements of the Pparg locus.

Main Results:

  • BRD4 dynamically redistributes to de novo super-enhancers during adipogenesis.
  • BET protein inhibition disrupts BRD4 occupancy and Pparg/Cebpa transcription, blocking adipogenesis.
  • Silencing of BRD4-occupied enhancers impairs Pparg expression and adipogenesis.

Conclusions:

  • BRD4 acts as a crucial coactivator for PPARγ and C/EBPα during adipogenesis.
  • BET bromodomain proteins are essential, time- and context-dependent coactivators of the adipocyte cell state transition.
  • De novo super-enhancers are critical for regulating adipocyte differentiation gene expression.