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BET bromodomain proteins regulate enhancer function during adipogenesis.

BET bromodomain proteins regulate enhancer function during adipogenesis.
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Brown JD, Feldman ZB, Doherty SP, Reyes JM, Rahl PB, Lin CY, Sheng Q, Duan Q, Federation AJ, Kung AL, Haldar SM, Young RA, Plutzky J, Bradner JE,


Brown JD, Feldman ZB, Doherty SP, Reyes JM, Rahl PB, Lin CY, Sheng Q, Duan Q, Federation AJ, Kung AL, Haldar SM, Young RA, Plutzky J, Bradner JE, (click to view)

Brown JD, Feldman ZB, Doherty SP, Reyes JM, Rahl PB, Lin CY, Sheng Q, Duan Q, Federation AJ, Kung AL, Haldar SM, Young RA, Plutzky J, Bradner JE,

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Proceedings of the National Academy of Sciences of the United States of America 2018 02 14() pii 10.1073/pnas.1711155115

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 ofand, thereby blocking adipogenesis. Furthermore, silencing of these BRD4-occupied distal regulatory elements at thelocus by CRISPRi demonstrates a critical role for these enhancers in the control ofgene expression and adipogenesis in 3T3L1s. Together, these data establish BET bromodomain proteins as time- and context-dependent coactivators of the adipocyte cell state transition.

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