Brown, Jonathan D.Feldman, Zachary B.Doherty, Sean P.Reyes, Jaime M.Rahl, Peter B.Lin, Charles Y.Sheng, QuanhuDuan, QiongFederation, Alexander J.Kung, Andrew L.Haldar, Saptarsi M.Young, Richard A.Plutzky, JorgeBradner, James E.2018-04-192018Brown, J. D., Z. B. Feldman, S. P. Doherty, J. M. Reyes, P. B. Rahl, C. Y. Lin, Q. Sheng, et al. 2018. “BET bromodomain proteins regulate enhancer function during adipogenesis.” Proceedings of the National Academy of Sciences of the United States of America 115 (9): 2144-2149. doi:10.1073/pnas.1711155115. http://dx.doi.org/10.1073/pnas.1711155115.http://nrs.harvard.edu/urn-3:HUL.InstRepos:35981980Developmental 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 bromodomain-containing 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.en-USCell BiologychromatincoactivatorBET bromodomainadipogenesistranscriptionJournal Article2018-04-1910.1073/pnas.1711155115