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BRD4 loading at the transcription start site mediates pause-release and underlies the disproportionate transcriptional response to BET bromodomain inhibition

ABSTRACT: BRD4 loading at the transcription start site mediates pause-release and underlies the disproportionate transcriptional response to BET bromodomain inhibition

PROVIDER: PRJNA288701 | ENA |

REPOSITORIES: ENA

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BRD4 loading at the transcription start site mediates pause-release and underlies the disproportionate transcriptional response to BET bromodomain inhibition [GRO-Seq]

Project description:BET bromodomain inhibition (BETi) abrogates cancer cell growth by disrupting oncogenic gene expression. BRD4 loading at enhancers has been suggested to mediate pause-release and underlie the selective transcriptional response to BETi. Here, we utilized GRO-seq coupled with ChIP-seq to assess the association between gene control elements and the transcriptional response to BETi. Genes immediately down-regulated by BETi display a marked pause-release defect with a minimal impact on transcript elongation within the gene body. Surprisingly, we find that BRD4 at super-enhancers does not render its associated genes or enhancer RNAs preferentially sensitive to BETi. In contrast, disproportionate loading of BRD4 at transcription start sites (TSS) correlates with the transcriptional response to BETi. Moreover, BRD4 loading at TSSs, but not enhancers, is associated with enhanced promoter-proximal pausing following BETi. Our findings stress a mechanistic role of promoter-associated BRD4 in pause-release and suggest that BRD4 loading at the TSS drives the selective transcriptional response to BETi.

2023-01-06 | GSE70449 | GEO

BRD4 loading at the transcription start site mediates pause-release and underlies the disproportionate transcriptional response to BET bromodomain inhibition [ChIP-Seq]

2023-01-06 | GSE70448 | GEO

BRD4 loading at the transcription start site mediates pause-release and underlies the disproportionate transcriptional response to BET bromodomain inhibition [RNA-Seq]

2023-01-06 | GSE70447 | GEO

Brd4 and JMJD6-associated Anti-pause Enhancers in Regulation of Transcriptional Pause Release

Project description:Distal enhancers characterized by H3K4me1 mark play critical roles in developmental and transcriptional programs. However, potential roles of specific distal regulatory elements in regulating RNA Polymerase II (Pol II) promoter-proximal pause release remain poorly investigated. Here we report that a unique cohort of jumonji C domain-containing protein 6 (JMJD6) and bromodomain-containing protein 4 (Brd4) co-bound distal enhancers, termed anti-pause enhancers (A-PEs), regulate promoter-proximal pause release of a large subset of transcription units via long-range interactions. Brd4-dependent JMJD6 recruitment on A-PEs mediates erasure of H4R3me2(s), which is directly read by 7SK snRNA, and decapping/demethylation of 7SK snRNA, ensuring the dismissal of the 7SKsnRNA/HEXIM inhibitory complex. The interactions of both JMJD6 and Brd4 with the P-TEFb complex permit its activation and pause release of regulated coding genes. The functions of JMJD6/ Brd4-associated dual histone and RNA demethylase activity on anti-pause enhancers have intriguing implications for these proteins in development, homeostasis and disease. All Gro-seq(s) were designed to reveal the transcriptional targets of JMJD6 and Brd4, and assess the role of JMJD6 and Brd4 in Pol II promoter-proximal pause release. All ChIP-seq(s) were designed to understand the unique features, associated molecular mechanisms and functions of the anti-pause enhancers (A-PEs) discovered in the current study.

2014-01-14 | E-GEOD-51633 | biostudies-arrayexpress

Brd4 and JMJD6-associated Anti-pause Enhancers in Regulation of Transcriptional Pause Release

2014-01-14 | GSE51633 | GEO

Distinct layers of BRD4-PTEFb reveal bromodomain-independent function in transcriptional regulation

Project description:The BET family protein BRD4, which forms the CDK9-containing BRD4-PTEFb complex, is considered to be a master regulator of RNA polymerase II (Pol II) pause release. Because its tandem bromodomains interact with acetylated histone lysine residues, it has long been thought that BRD4 requires these bromodomains for its recruitment to chromatin and transcriptional regulatory function. Here, using rapid depletion and genetic complementation with domain deletion mutants, we demonstrate that BRD4 bromodomains are dispensable for Pol II pause release. A minimal, bromodomain-less C-terminal BRD4 fragment containing the PTEFb-interacting C-terminal motif (CTM) is instead both necessary and sufficient to mediate Pol II pause release in the absence of full-length BRD4. Although BRD4-PTEFb can associate with chromatin through acetyl recognition, our results indicate that a distinct, active BRD4-PTEFb population functions to regulate transcription independently of bromodomain-mediated chromatin association. These findings may enable more effective pharmaceutical modulation of BRD4-PTEFb activity.

2023-07-14 | GSE232869 | GEO

Homo sapiens

Project description:BRD4 loading at the transcription start site mediates pause-release and underlies the disproportionate transcriptional response to BET bromodomain inhibition [GRO-Seq]

| PRJNA288702 | ENA

Homo sapiens

Project description:BRD4 loading at the transcription start site mediates pause-release and underlies the disproportionate transcriptional response to BET bromodomain inhibition [ChIP-Seq]

| PRJNA288703 | ENA

Homo sapiens

Project description:BRD4 loading at the transcription start site mediates pause-release and underlies the disproportionate transcriptional response to BET bromodomain inhibition [RNA-Seq]

| PRJNA288704 | ENA

BRD4 loading at the transcription start site mediates pause-release and underlies the disproportionate transcriptional response to BET bromodomain inhibition

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-01-06 | GSE70450 | GEO