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Evf2 lncRNA/BRG1/DLX1 interactions reveal RNA-dependent inhibition of chromatin remodeling.
- Source :
-
Development (Cambridge, England) [Development] 2015 Aug 01; Vol. 142 (15), pp. 2641-52. Date of Electronic Publication: 2015 Jul 02. - Publication Year :
- 2015
-
Abstract
- Transcription-regulating long non-coding RNAs (lncRNAs) have the potential to control the site-specific expression of thousands of target genes. Previously, we showed that Evf2, the first described ultraconserved lncRNA, increases the association of transcriptional activators (DLX homeodomain proteins) with key DNA enhancers but represses gene expression. In this report, mass spectrometry shows that the Evf2-DLX1 ribonucleoprotein (RNP) contains the SWI/SNF-related chromatin remodelers Brahma-related gene 1 (BRG1, SMARCA4) and Brahma-associated factor (BAF170, SMARCC2) in the developing mouse forebrain. Evf2 RNA colocalizes with BRG1 in nuclear clouds and increases BRG1 association with key DNA regulatory enhancers in the developing forebrain. While BRG1 directly interacts with DLX1 and Evf2 through distinct binding sites, Evf2 directly inhibits BRG1 ATPase and chromatin remodeling activities. In vitro studies show that both RNA-BRG1 binding and RNA inhibition of BRG1 ATPase/remodeling activity are promiscuous, suggesting that context is a crucial factor in RNA-dependent chromatin remodeling inhibition. Together, these experiments support a model in which RNAs convert an active enhancer to a repressed enhancer by directly inhibiting chromatin remodeling activity, and address the apparent paradox of RNA-mediated stabilization of transcriptional activators at enhancers with a repressive outcome. The importance of BRG1/RNA and BRG1/homeodomain interactions in neurodevelopmental disorders is underscored by the finding that mutations in Coffin-Siris syndrome, a human intellectual disability disorder, localize to the BRG1 RNA-binding and DLX1-binding domains.<br /> (© 2015. Published by The Company of Biologists Ltd.)
- Subjects :
- Abnormalities, Multiple genetics
Animals
Base Sequence
Chromatin Assembly and Disassembly genetics
Chromatin Immunoprecipitation
DNA Helicases genetics
DNA Primers genetics
Face abnormalities
Hand Deformities, Congenital genetics
Humans
Immunohistochemistry
In Situ Hybridization, Fluorescence
Intellectual Disability genetics
Mass Spectrometry
Mice
Micrognathism genetics
Molecular Sequence Data
Neck abnormalities
Nuclear Proteins genetics
RNA, Long Noncoding genetics
Sequence Analysis, RNA
Transcription Factors genetics
Chromatin Assembly and Disassembly physiology
DNA Helicases metabolism
Gene Expression Regulation genetics
Homeodomain Proteins metabolism
Nuclear Proteins metabolism
Prosencephalon embryology
RNA, Long Noncoding metabolism
Ribonucleoproteins metabolism
Transcription Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1477-9129
- Volume :
- 142
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- Development (Cambridge, England)
- Publication Type :
- Academic Journal
- Accession number :
- 26138476
- Full Text :
- https://doi.org/10.1242/dev.126318