Year: 2018
Type: article
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 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.
Institutions: Vanderbilt University Medical Center, Baylor College of Medicine, Whitehead Institute for Biomedical Research, Vanderbilt University, Central South University, Xiangya Hospital Central South University, Harvard University, Dana-Farber Cancer Institute, University of California, San Francisco, Columbia University Irving Medical Center, Massachusetts Institute of Technology, Brigham and Women's Hospital
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Awards: G1153102669, G1605025194, G2835674304, Hepatic Lipase, PPAR-delta and Fatty Acid Metabolism, G3959418336, BET Bromodomain proteins as Novel Epigenetic Targets for prevention of Intimal Hyperplasia after Vascular Surgery, Program in Human and Molecular Genetics, G6415911352, G6976304365, G9000087076, G9000186899, Molecular and Cellular Basis for Digestive Diseases, Integrated Epithelial and Muscosal Biology
OpenAlex ID: W2790938076