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 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 bromodomaincontaining 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.chromatin | coactivator | BET bromodomain | adipogenesis | transcription

Partnership between epigenetic reader BRD4 and transcription factor CEBPD

“…To the best of our knowledge, the BRD4/CEBPD partnership was not previously recognized, likely due to a paucity of information on CEBPD in contrast to extensively studied CEBPA. A BRD4 functional association with CEBPA in adipogenesis was recently reported 28,30 , highlighting differential and contextual functions of different CEBP family members.…”

“…A unique interesting finding in this study is that CEBPD promotes its own transcription in SMCs, appearing to fit the concept of master TF. Among over a thousand TFs, a small number of socalled master TFs are critically important for cell identity, in other words, cell type or state 7,28,29 . Exemplary of master TFs, c-Myc is a powerful driver of oncogenic cell sate transitions 7 .…”

BET Bromodomain Proteins Regulate Transcriptional Reprogramming in Genetic Dilated Cardiomyopathy

“…(30,31) SE activation alters the cellular transcriptome and can permit cell-state transition. (20,32) In the heart, this manifests as pathologic gene expression and the transdifferentiation of quiescent fibroblasts to myofibroblasts. (29) Precisely how this locus-specific flux of BRD4 to DCM-specific SEs occurs has not previously been elucidated in the heart.…”

BRD2 regulation of sigma-2 receptor expression upon cytosolic cholesterol deprivation

“…BETs inhibition was initially shown to be highly effective in blocking transcription programs of inflammation 28 and oncogenic proliferation 29 . The importance of BET biology was then extended to stem cell differentiation, hematopoiesis, synaptic plasticity 12 , and recently, also adipogenesis 10,30 . Most recently, BRD4 was found to regulate intra-nuclear/cellular processes as well, such as chromatin architectural remodeling 31 and autophagy 11 .…”

“…Curiously, whether BETs are directly involved in cholesterol homeostasis remained unclear 12 . Relevant to this question, recent studies identified a crucial role of BRD4 in adipogenesis 10 . We were thus encouraged to explore whether BRD4 regulates the expression of S2R, a novel modulator of cholesterol transport 2 .…”