BET bromodomain proteins regulate enhancer function during adipogenesis
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Author(s)
Brown, Jonathan D.
Feldman, Zachary B.
Doherty, Sean P.
Reyes, Jaime M.
Rahl, Peter B.
Lin, Charles Y.
Sheng, Quanhu
Duan, Qiong
Federation, Alexander J.
Kung, Andrew L.
Date Issued
February 2017
Journal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences (U.S.)
Citation
Brown, Jonathan D. et al. “BET Bromodomain Proteins Regulate Enhancer Function During Adipogenesis.” Proceedings of the National Academy of Sciences 115, 9 (February 2018): 2144–2149 © 2018 National Academy of Sciences
Version
Final published version
Abstract
Developmental transitions are guided by master regulatory transcription factors. During adipogenesis, a transcriptional cascade culminates in the expression of PPARγ and C/EBPα, which orchestrate activation of the adipocyte gene expression program. However, the coactivators controlling PPARγ and C/EBPα expression are less well characterized. Here, we show the bromodomaincontaining protein, BRD4, regulates transcription of PPARγ and C/EBPα. Analysis of BRD4 chromatin occupancy reveals that induction of adipogenesis in 3T3L1 fibroblasts provokes dynamic redistribution of BRD4 to de novo super-enhancers proximal to genes controlling adipocyte differentiation. Inhibition of the bromodomain and extraterminal domain (BET) family of bromodomain-containing proteins impedes BRD4 occupancy at these de novo enhancers and disrupts transcription of Pparg and Cebpa, thereby blocking adipogenesis. Furthermore, silencing of these BRD4-occupied distal regulatory elements at the Pparg locus by CRISPRi demonstrates a critical role for these enhancers in the control of Pparg gene expression and adipogenesis in 3T3L1s. Together, these data establish BET bromodomain proteins as time- and context-dependent coactivators of the adipocyte cell state transition. Keywords: chromatin; coactivator; BET bromodomain; adipogenesis; transcription
MIT Department
Massachusetts Institute of Technology. Department of Biology
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DOI of Published Version
https://doi.org/10.1073/PNAS.1711155115
