BET bromodomain proteins regulate enhancer function during adipogenesis.

ABSTRACT: Developmental transitions are guided by master regulatory transcription factors. During adipogenesis, a transcriptional cascade culminates in the expression of PPAR? and C/EBP?, which orchestrate activation of the adipocyte gene expression program. However, the coactivators controlling PPAR? and C/EBP? expression are less well characterized. Here, we show the bromodomain-containing protein, BRD4, regulates transcription of PPAR? and C/EBP?. 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.

SUBMITTER: Brown JD 

PROVIDER: S-EPMC5834672 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature