| First Author | Brown JD | Year | 2018 |
| Journal | Proc Natl Acad Sci U S A | Volume | 115 |
| Issue | 9 | Pages | 2144-2149 |
| PubMed ID | 29444854 | Mgi Jnum | J:265775 |
| Mgi Id | MGI:6120596 | Doi | 10.1073/pnas.1711155115 |
| Citation | Brown JD, et al. (2018) BET bromodomain proteins regulate enhancer function during adipogenesis. Proc Natl Acad Sci U S A 115(9):2144-2149 |
| abstractText | Developmental transitions are guided by master regulatory transcription factors. During adipogenesis, a transcriptional cascade culminates in the expression of PPARgamma and C/EBPalpha, which orchestrate activation of the adipocyte gene expression program. However, the coactivators controlling PPARgamma and C/EBPalpha expression are less well characterized. Here, we show the bromodomain-containing protein, BRD4, regulates transcription of PPARgamma and C/EBPalpha. 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. |
