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Long Noncoding RNA NEAT1 Acts as a Molecular Switch for BRD4 Transcriptional Activity and Mediates Repression of BRD4/WDR5 Target Genes.
- Source :
-
Molecular cancer research : MCR [Mol Cancer Res] 2021 May; Vol. 19 (5), pp. 799-811. Date of Electronic Publication: 2021 Feb 05. - Publication Year :
- 2021
-
Abstract
- 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.<br /> (©2021 American Association for Cancer Research.)
- Subjects :
- Cell Cycle Proteins metabolism
Cell Line, Tumor
Humans
Intracellular Signaling Peptides and Proteins metabolism
Melanoma metabolism
Melanoma pathology
RNA, Long Noncoding metabolism
Transcription Factors metabolism
Transcriptional Activation
Cell Cycle Proteins genetics
Intracellular Signaling Peptides and Proteins genetics
Melanoma genetics
RNA, Long Noncoding genetics
Transcription Factors genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3125
- Volume :
- 19
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Molecular cancer research : MCR
- Publication Type :
- Academic Journal
- Accession number :
- 33547232
- Full Text :
- https://doi.org/10.1158/1541-7786.MCR-20-0324