Activating RNAs associate with Mediator to enhance chromatin architecture and transcription

By Fan Lai, U. A. Orom, M. Cesaroni, M. Beringer, D. Taatjes, G. Blobel, R. Shiekhattar. Nature, 2013

812 citations recorded by the source corpus.

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.

View Paper: https://www.semanticscholar.org/paper/981852dd1d3560ae948eb464dcb995b9a1e16f05

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The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

1. F. Marchese
2. M. Kaikkonen
3. Ivan Raimondi
4. Alexander Stark
5. Carlo Maria Croce
6. S. Heinz
7. Maite Huarte
8. C. Romanoski

Citations in the corpus

• Long noncoding RNA in prostate, bladder, and kidney cancer. (2014, background): “At present, a cis-activating role and an enhancer-like function is also anticipated for a large set of lncRNAs located adjacent to cancer-related protein-coding genes that act a step further in gene transcription by promoting transcriptional elongation [24].”
• Transcriptional enhancers: from properties to genome-wide predictions (2014, background): “Finally, the biological function of eRNAs remains unclear, and there is no consensus about whether they mediate specific bio-chemical functions 92 , whether they are involved in or required for the establishment and/or maintenance of Chromatin interaction analysis with paired-end tag sequencing…”
• Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription (2013, background): “Recent studies suggest functional roles of eRNAs themselves in contributing to enhancer activity, at least in part by promoting enhancer-promoter looping and regulating mediator recruitment (Lai et al., 2013; Lam et al., 2013; Li et al., 2013; Melo et al., 2013).”
• Transcriptional and Post-transcriptional Gene Regulation by Long Non-coding RNA (2017, background): “In common with both DNA enhancers and eRNAs, gene activation mediated by the ncRNA-a requires a change in chromosomal conformation to bring the ncRNA-a locus close to the promoter of its target gene [72].”
• lincRNAs: Genomics, Evolution, and Mechanisms (2013, unknown): “Examples of other cis-regulatory lincRNAs include ncRNA-a1-7,Hottip, andMistral, the perturbation of which leads to decreased expression of some nearby genes (Ørom et al., 2010; Bertani et al., 2011; Wang et al., 2011; Lai et al., 2013).”
• Transcription factors interact with RNA to regulate genes (2022, background): “The noncoding RNAs produced from enhancers and promoters are known to affect gene expression (Kaikkonen and Adelman, 2018), and plausible mechanisms by which these RNA species could influence gene regulation have been proposed to include binding to cofactors and chromatin regulators (Bose et al., 20”
• The multidimensional mechanisms of long noncoding RNA function (2017, background): “H3, catalysing the phosphorylation of the serine 10 (H3S10) [53].”