BRD4: a general regulator of transcription elongation

Abstract

Transcription elongation by RNA polymerase II (Pol II) has emerged as a regulatory hub in gene expression. A key control point occurs during early transcription elongation when Pol II pauses in the promoter-proximal region at the majority of genes in mammalian cells and at a large set of genes in Drosophila . An increasing number of trans -acting factors have been linked to promoter-proximal pausing. Some factors help to establish the pause, whereas others are required for the release of Pol II into productive elongation. A dysfunction of this elongation control point leads to aberrant gene expression and can contribute to disease development. The BET bromodomain protein BRD4 has been implicated in elongation control. However, only recently direct BRD4-specific functions in Pol II transcription elongation have been uncovered. This mainly became possible with technological advances that allow selective and rapid ablation of BRD4 in cells along with the availability of approaches that capture the immediate consequences on nascent transcription. This review sheds light on the experimental breakthroughs that led to the emerging view of BRD4 as a general regulator of transcription elongation.

The bromodomain inhibitor JQ1 is a molecular glue targeting centromeres

“…In this study we identify an unexpected enrichment of the BET bromodomain protein BRD4 15 at centromeres and demonstrate a new function for this protein in the regulation of centromeric cohesion 16 . We then demonstrate that the BET bromodomain inhibitor JQ1 17 further recruits BRD4 to the centromere, in contrast to its canonical mechanism antagonising the association of BRD4 with chromatin 18 .…”

“…We also identified 19 high confidence new centromere protein candidates, which met one or both of the following criteria: 1) more than two-fold enriched compared to corresponding control, 2) in the top 500 samples by percent of reads aligned to the centromere. Within the new centromere candidates was BRD4, a key protein in the organization of super-enhancers, transcription elongation and interphase genome organization 15, 25, 28 .…”

“…The discovery of the presence and drug-induced increase of BRD4 at centromeres is remarkable. Typically, BRD4 is considered as a regulator of genes and enhancers 15 , but centromeric regions lack these elements and are mostly transcriptionally inactive 8, 29 . Recent studies have revealed that BRD4 also plays a role in the organisation of the interphase genome by promoting cohesin loading at TAD boundaries, indicating a role in contemporary theories of genome organisation through chromatin loop extrusion.…”

BET Bromodomain Inhibitors: Novel Design Strategies and Therapeutic Applications

“…BET proteins are transcription regulators. Brd4 is known to recruit PTEF-b (positive transcription elongation factor which is a multi-protein complex essential for transcription regulation) to sites of active transcription of cell growth-promoting genes such as MYC and NUT [ 27 , 28 ]. During transcription elongation, Brd4 directs the proper nuclear localization and activation of PTEF-b to phosphorylate RNA polymerase II [ 29 ].…”

Regulation of programmed cell death by Brd4

“…Genome wide studies indicate that Brd4 is present at a significant proportion of active promoter and enhancer regions, including super-enhancers [ 2 ]. Brd4 recruits positive transcription elongation factor b (P-TEFb) to the promoter-proximal regions for phosphorylation of RNA polymerase II, leading to the start of transcription elongation [ 3 ]. Binding to hyperacetylated chromatin regions, Brd4 recruits the mediator complex and chromatin modifiers to facilitate the assembly of a large protein complex, which forms a bridge between enhancer and promoter, promoting and stabilizing the binding of RNA polymerase II [ 4 , 5 ].…”