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  Activating RNAs associate with Mediator to enhance chromatin architecture and transcription

Lai, F., Ørom, U. A., Cesaroni, M., Beringer, M., Taatjes, D. J., Blobel, G. A., et al. (2013). Activating RNAs associate with Mediator to enhance chromatin architecture and transcription. Nature, 494(7438), 497-501. doi:10.1038/nature11884.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0019-1122-4 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0019-1124-F
Genre: Journal Article

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 Creators:
Lai, F., Author
Ørom, U. A.1, Author              
Cesaroni, M., Author
Beringer, M., Author
Taatjes, D. J., Author
Blobel, G. A., Author
Shiekhattar, R., Author
Affiliations:
1Long non-coding RNA (Ulf Andersson Ørom), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society, Ihnestr. 73, 14195 Berlin, Germany, ou_1479659              

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Free keywords: Agenesis of Corpus Callosum/genetics Anus, Imperforate/genetics Chromatin/chemistry/*genetics/*metabolism Constipation/genetics Gene Knockdown Techniques Genes, Reporter/genetics Humans Mediator Complex/chemistry/deficiency/genetics/*metabolism Mental Retardation, X-Linked/genetics Molecular Conformation Muscle Hypotonia/congenital/genetics Protein Subunits/genetics/metabolism RNA, Long Noncoding/*genetics/*metabolism RNA-Binding Proteins/chemistry/genetics/metabolism *Transcription, Genetic/genetics
 Abstract: Recent advances in genomic research have revealed the existence of a large number of transcripts devoid of protein-coding potential in multiple organisms. Although the functional role for long non-coding RNAs (lncRNAs) has been best defined in epigenetic phenomena such as X-chromosome inactivation and imprinting, different classes of lncRNAs may have varied biological functions. We and others have identified a class of lncRNAs, termed ncRNA-activating (ncRNA-a), that function to activate their neighbouring genes using a cis-mediated mechanism. To define the precise mode by which such enhancer-like RNAs function, we depleted factors with known roles in transcriptional activation and assessed their role in RNA-dependent activation. Here we report that depletion of the components of the co-activator complex, Mediator, specifically and potently diminished the ncRNA-induced activation of transcription in a heterologous reporter assay using human HEK293 cells. In vivo, Mediator is recruited to ncRNA-a target genes and regulates their expression. We show that ncRNA-a interact with Mediator to regulate its chromatin localization and kinase activity towards histone H3 serine 10. The Mediator complex harbouring disease- displays diminished ability to associate with activating ncRNAs. Chromosome conformation capture confirmed the presence of DNA looping between the ncRNA-a loci and its targets. Importantly, depletion of Mediator subunits or ncRNA-a reduced the chromatin looping between the two loci. Our results identify the human Mediator complex as the transducer of activating ncRNAs and highlight the importance of Mediator and activating ncRNA association in human disease.

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Language(s): eng - English
 Dates: 2013-02-172013-02-28
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1038/nature11884
ISSN: 1476-4687 (Electronic)0028-0836 (Print)
URI: http://www.ncbi.nlm.nih.gov/pubmed/23417068
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Title: Nature
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 494 (7438) Sequence Number: - Start / End Page: 497 - 501 Identifier: ISSN: 0028-0836
CoNE: https://pure.mpg.de/cone/journals/resource/954925427238