Journal
MOLECULAR CANCER RESEARCH
Volume 19, Issue 5, Pages 799-811Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-20-0324
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Funding
- Fondazione Umberto Veronesi
- Associazione Italiana per la Ricerca sul Cancro [AIRC IG 21772]
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BRD4 interacts with various long noncoding RNAs, with NEAT1 inhibiting its transcriptional activity and forming a complex with WDR5. Treatment with BET inhibitors dissociates NEAT1 from the complex, activating the transcriptional activity of BRD4/WDR5. NEAT1 can also inhibit EZH2, cooperatively increasing transcriptional activation.
BRD4 is an epigenome reader known to exert key roles at the interface between chromatin remodeling and transcriptional regulation, and is primarily known for its role in promoting gene expression. In selective contexts, however, BRD4 may work as negative regulator of transcription. Here, we reported that BRD4 binds several long noncoding RNAs (lncRNA). Among these, the lncRNA NEAT1 was found to interfere with BRD4 transcriptional activity. Mechanistically, lncNEAT1 forms a complex with BRD4 and WDR5 and maintains them in a low-activity state. Treatment with Bromodomains and Extraterminal (BET) inhibitor caused the lncRNA NEAT1 to dissociate from the BRD4/WDR5 complex, restored the acetyl-transferase capacity of BRD4, and restored the availability of WDR5 to promote histone trimethylation, thereby promoting BRD4/WDR5 transcriptional activity and activation of target gene expression. In addition, the lncRNA NEAT1 then became available to bind and to inhibit EZH2, cooperatively increasing transcriptional activation. Implications: Our results revealed an epigenetic program that involves the interaction between the lncRNA NEAT1 and BRD4, functioning as a molecular switch between BRD4's activator and repressor chromatin complexes.
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