Emerging roles of BET proteins in transcription and co‐transcriptional RNA processing

Abstract

Transcription by RNA polymerase II (Pol II) gives rise to all nuclear protein‐coding and a large set of non‐coding RNAs, and is strictly regulated and coordinated with RNA processing. Bromodomain and extraterminal (BET) family proteins including BRD2, BRD3, and BRD4 have been implicated in the regulation of Pol II transcription in mammalian cells. However, only recent technological advances have allowed the analysis of direct functions of individual BET proteins with high precision in cells. These studies shed new light on the molecular mechanisms of transcription control by BET proteins challenging previous longstanding views. The most studied BET protein, BRD4, emerges as a master regulator of transcription elongation with roles also in coupling nascent transcription with RNA processing. In contrast, BRD2 is globally required for the formation of transcriptional boundaries to restrict enhancer activity to nearby genes. Although these recent findings suggest non‐redundant functions of BRD4 and BRD2 in Pol II transcription, more research is needed for further clarification. Little is known about the roles of BRD3. Here, we illuminate experimental work that has initially linked BET proteins to Pol II transcription in mammalian cells, outline main methodological breakthroughs that have strongly advanced the understanding of BET protein functions, and discuss emerging roles of individual BET proteins in transcription and transcription‐coupled RNA processing. Finally, we propose an updated model for the function of BRD4 in transcription and co‐transcriptional RNA maturation. This article is categorized under: RNA Processing > 3′ End Processing RNA Processing > Splicing Regulation/Alternative Splicing

The human papillomavirus late life cycle and links to keratinocyte differentiation

“…129 The E2 binding partner, BRD4 can control alternative splicing through direct interaction with the spliceosome during RNA Pol II transcription. 131 Therefore, BRD4, or its short form BRD4S, could control late RNA splicing via E2. 61 E2 itself can bind splicing factors therefore E2 could regulate cellular or viral constitutive and alternative splicing.…”

“…Since SRSF3 is required for HPV16 late gene expression, this means that E2 indirectly controls the expression of the capsid proteins 129 . The E2 binding partner, BRD4 can control alternative splicing through direct interaction with the spliceosome during RNA Pol II transcription 131 . Therefore, BRD4, or its short form BRD4S, could control late RNA splicing via E2 61 .…”

BRD4: a general regulator of transcription elongation

“…Although pan-BET bromodomain inhibitors have been a powerful tool for the analysis of the molecular mechanisms of transcription regulation, they also have limitations ( Figure 2 ) [ 49 ]. One main limitation is that BET bromodomain inhibition results in incomplete phenotypes masking the cellular roles of BET proteins.…”

“…BRD4 has been implicated in the regulation of Pol II transcription elongation [ 49 , 50 ]. BRD4 belongs together with BRD2, BRD3 and BRDT to the mammalian BET bromodomain protein family [ 49 , 51 , 52 ].…”

“…BRD4 has been implicated in the regulation of Pol II transcription elongation [ 49 , 50 ]. BRD4 belongs together with BRD2, BRD3 and BRDT to the mammalian BET bromodomain protein family [ 49 , 51 , 52 ]. BRD2/3/4 are ubiquitously expressed in all mammalian cell and tissue types investigated so far [ 53 , 54 ], whereas the expression of BRDT is restricted to testis [ 55 ].…”