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      Direct Interactions with Nascent Transcripts Is Potentially a Common Targeting Mechanism of Long Non-Coding RNAs

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      1 , 2 , 1 , 2 , *
      Genes
      MDPI
      long non-coding RNAs, RNA-RNA interactions, nascent transcripts, gene regulation

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          Abstract

          Although thousands of mammalian long non-coding RNAs (lncRNAs) have been reported in the last decade, their functional annotation remains limited. A wet-lab approach to detect functions of a novel lncRNA usually includes its knockdown followed by RNA sequencing and identification of the deferentially expressed genes. However, identification of the molecular mechanism(s) used by the lncRNA to regulate its targets frequently becomes a challenge. Previously, we developed the ASSA algorithm that detects statistically significant inter-molecular RNA-RNA interactions. Here we designed a workflow that uses ASSA predictions to estimate the ability of an lncRNA to function via direct base pairing with the target transcripts (co- or post-transcriptionally). The workflow was applied to 300+ lncRNA knockdown experiments from the FANTOM6 pilot project producing statistically significant predictions for 71 unique lncRNAs (104 knockdowns). Surprisingly, the majority of these lncRNAs were likely to function co-transcriptionally, i.e., hybridize with the nascent transcripts of the target genes. Moreover, a number of the obtained predictions were supported by independent iMARGI experimental data on co-localization of lncRNA and chromatin. We detected an evolutionarily conserved lncRNA CHASERR (AC013394.2 or LINC01578) that could regulate target genes co-transcriptionally via interaction with a nascent transcript by directing CHD2 helicase. The obtained results suggested that this nuclear lncRNA may be able to activate expression of the target genes in trans by base-pairing with the nascent transcripts and directing the CHD2 helicase to the regulated promoters leading to open the chromatin and active transcription. Our study highlights the possible importance of base-pairing between nuclear lncRNAs and nascent transcripts for the regulation of gene expression.

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          Most cited references35

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          Unique features of long non-coding RNA biogenesis and function.

          Long non-coding RNAs (lncRNAs) are a diverse class of RNAs that engage in numerous biological processes across every branch of life. Although initially discovered as mRNA-like transcripts that do not encode proteins, recent studies have revealed features of lncRNAs that further distinguish them from mRNAs. In this Review, we describe special events in the lifetimes of lncRNAs - before, during and after transcription - and discuss how these events ultimately shape the unique characteristics and functional roles of lncRNAs.
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            The functions and unique features of long intergenic non-coding RNA

            Long intergenic non-coding RNA (lincRNA) genes have diverse features that distinguish them from mRNA-encoding genes and exercise functions such as remodelling chromatin and genome architecture, RNA stabilization and transcription regulation, including enhancer-associated activity. Some genes currently annotated as encoding lincRNAs include small open reading frames (smORFs) and encode functional peptides and thus may be more properly classified as coding RNAs. lincRNAs may broadly serve to fine-tune the expression of neighbouring genes with remarkable tissue specificity through a diversity of mechanisms, highlighting our rapidly evolving understanding of the non-coding genome.
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              • Article: not found

              Modular regulatory principles of large non-coding RNAs.

              It is clear that RNA has a diverse set of functions and is more than just a messenger between gene and protein. The mammalian genome is extensively transcribed, giving rise to thousands of non-coding transcripts. Whether all of these transcripts are functional is debated, but it is evident that there are many functional large non-coding RNAs (ncRNAs). Recent studies have begun to explore the functional diversity and mechanistic role of these large ncRNAs. Here we synthesize these studies to provide an emerging model whereby large ncRNAs might achieve regulatory specificity through modularity, assembling diverse combinations of proteins and possibly RNA and DNA interactions.
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                Author and article information

                Journal
                Genes (Basel)
                Genes (Basel)
                genes
                Genes
                MDPI
                2073-4425
                10 December 2020
                December 2020
                : 11
                : 12
                : 1483
                Affiliations
                [1 ]Research Center of Biotechnology, Institute of Bioengineering, Russian Academy of Science, 119071 Moscow, Russia; ivan.antonov@ 123456gatech.edu
                [2 ]Department of Biological and Medical Physics, Moscow Institute of Physics and Technology, Dolgoprudny, 141701 Moscow Region, Russia
                Author notes
                Author information
                https://orcid.org/0000-0002-8330-6907
                https://orcid.org/0000-0002-7587-1666
                Article
                genes-11-01483
                10.3390/genes11121483
                7764144
                33321875
                2dcfe2e8-e34b-426e-b43a-0a6bd307f77f
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 24 October 2020
                : 04 December 2020
                Categories
                Article

                long non-coding rnas,rna-rna interactions,nascent transcripts,gene regulation

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