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BRD4 assists elongation of both coding and enhancer RNAs by interacting with acetylated histones
Tomohiko Kanno1, Yuka Kanno2, Gary LeRoy3
11] Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA. [2] Program in Genomics of Differentiation, National Institutes of Child Health and Human Development, Bethesda, Maryland, USA.
Abstract:
Small-molecule BET inhibitors interfere with the epigenetic interactions between acetylated histones and the bromodomains of the BET family proteins, including BRD4, and they potently inhibit growth of malignant cells by targeting cancer-promoting genes. BRD4 interacts with the pause-release factor P-TEFb and has been proposed to release RNA polymerase II (Pol II) from promoter-proximal pausing. We show that BRD4 occupies widespread genomic regions in mouse cells and directly stimulates elongation of both protein-coding transcripts and noncoding enhancer RNAs (eRNAs), in a manner dependent on bromodomain function. BRD4 interacts with elongating Pol II complexes and assists Pol II in progression through hyperacetylated nucleosomes by interacting with acetylated histones via bromodomains. On active enhancers, the BET inhibitor JQ1 antagonizes BRD4-associated eRNA synthesis. Thus, BRD4 is involved in multiple steps of the transcription hierarchy, primarily by facilitating transcript elongation both at enhancers and on gene bodies independently of P-TEFb.
Insights
BET inhibitors like JQ1 target cancer by blocking BRD4
Area of Science:
- Epigenetics
- Molecular Biology
- Cancer Biology
Background:
- BET inhibitors target bromodomain and extra-terminal domain (BET) proteins, including BRD4, which are crucial for cancer cell growth.
- BRD4 is implicated in releasing RNA polymerase II (Pol II) from promoter-proximal pausing, a key step in gene transcription.
Purpose of the Study:
- To investigate the role of BRD4 in transcriptional regulation, particularly its involvement in transcript elongation.
- To elucidate the mechanism by which BRD4 facilitates Pol II progression through chromatin.
Main Methods:
- Genomic occupancy studies in mouse cells to map BRD4 binding sites.
- Analysis of protein-coding and noncoding RNA synthesis in the presence and absence of BET inhibitors.
- Biochemical assays to study BRD4 interactions with Pol II and acetylated histones.
Main Results:
- BRD4 occupies extensive genomic regions and promotes the elongation of both protein-coding transcripts and enhancer RNAs (eRNAs) in a bromodomain-dependent manner.
- BRD4 interacts with elongating Pol II and facilitates its passage through hyperacetylated nucleosomes.
- The BET inhibitor JQ1 inhibits BRD4-associated eRNA synthesis on active enhancers.
Conclusions:
- BRD4 plays a multifaceted role in transcription, primarily by enhancing transcript elongation at both enhancers and gene bodies.
- This function of BRD4 is independent of the pause-release factor P-TEFb.
- BET inhibitors like JQ1 disrupt BRD4's function, offering a potential therapeutic strategy for cancers driven by BET proteins.
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