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      Expression and functions of long noncoding RNAs during human T helper cell differentiation

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          Abstract

          Long noncoding RNAs (lncRNAs) regulate an array of biological processes in cells and organ systems. Less is known about their expression and function in lymphocyte lineages. Here we have identified >2000 lncRNAs expressed in human T cell cultures and those which display a TH lineage specific pattern of expression and are intragenic or adjacent to TH lineage specific genes encoding proteins with immunologic functions. One lncRNA cluster selectively expressed by the effector TH2 lineage consists of four alternatively spliced transcripts that regulate expression of TH2 cytokines, IL-4, IL-5 and IL-13. Genes encoding this lncRNA cluster in humans overlap the RAD50 gene and thus are contiguous with the previously described TH2 locus control region (LCR) in the mouse. Given its genomic synteny with the TH2 LCR, we refer to this lncRNA cluster as TH2-LCR lncRNA.

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          Most cited references31

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          PhyloCSF: a comparative genomics method to distinguish protein coding and non-coding regions

          Motivation: As high-throughput transcriptome sequencing provides evidence for novel transcripts in many species, there is a renewed need for accurate methods to classify small genomic regions as protein coding or non-coding. We present PhyloCSF, a novel comparative genomics method that analyzes a multispecies nucleotide sequence alignment to determine whether it is likely to represent a conserved protein-coding region, based on a formal statistical comparison of phylogenetic codon models. Results: We show that PhyloCSF's classification performance in 12-species Drosophila genome alignments exceeds all other methods we compared in a previous study. We anticipate that this method will be widely applicable as the transcriptomes of many additional species, tissues and subcellular compartments are sequenced, particularly in the context of ENCODE and modENCODE, and as interest grows in long non-coding RNAs, often initially recognized by their lack of protein coding potential rather than conserved RNA secondary structures. Availability and Implementation: The Objective Caml source code and executables for GNU/Linux and Mac OS X are freely available at http://compbio.mit.edu/PhyloCSF Contact: mlin@mit.edu; manoli@mit.edu
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            A long noncoding RNA mediates both activation and repression of immune response genes.

            An inducible program of inflammatory gene expression is central to antimicrobial defenses. This response is controlled by a collaboration involving signal-dependent activation of transcription factors, transcriptional co-regulators, and chromatin-modifying factors. We have identified a long noncoding RNA (lncRNA) that acts as a key regulator of this inflammatory response. Pattern recognition receptors such as the Toll-like receptors induce the expression of numerous lncRNAs. One of these, lincRNA-Cox2, mediates both the activation and repression of distinct classes of immune genes. Transcriptional repression of target genes is dependent on interactions of lincRNA-Cox2 with heterogeneous nuclear ribonucleoprotein A/B and A2/B1. Collectively, these studies unveil a central role of lincRNA-Cox2 as a broad-acting regulatory component of the circuit that controls the inflammatory response.
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              The Xist lncRNA exploits three-dimensional genome architecture to spread across the X chromosome.

              Many large noncoding RNAs (lncRNAs) regulate chromatin, but the mechanisms by which they localize to genomic targets remain unexplored. We investigated the localization mechanisms of the Xist lncRNA during X-chromosome inactivation (XCI), a paradigm of lncRNA-mediated chromatin regulation. During the maintenance of XCI, Xist binds broadly across the X chromosome. During initiation of XCI, Xist initially transfers to distal regions across the X chromosome that are not defined by specific sequences. Instead, Xist identifies these regions by exploiting the three-dimensional conformation of the X chromosome. Xist requires its silencing domain to spread across actively transcribed regions and thereby access the entire chromosome. These findings suggest a model in which Xist coats the X chromosome by searching in three dimensions, modifying chromosome structure, and spreading to newly accessible locations.
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                Author and article information

                Journal
                101528555
                37539
                Nat Commun
                Nat Commun
                Nature communications
                2041-1723
                18 March 2015
                23 April 2015
                2015
                23 October 2015
                : 6
                : 6932
                Affiliations
                [1 ]Department of Medicine, Vanderbilt University School of Medicine, TN 37232
                [2 ]Department of Cancer Biology, Vanderbilt University School of Medicine, TN 37213
                [3 ]Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, TN 37232
                [4 ]Department of Mathematics, Vanderbilt University, TN 37240
                Author notes
                []Address correspondence to TMA, tom.aune@ 123456vanderbilt.edu
                Article
                NIHMS672869
                10.1038/ncomms7932
                4410435
                25903499
                40aace10-851e-4259-b649-85e4ac696181
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