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      Nuclear matrix protein Matrin3 regulates alternative splicing and forms overlapping regulatory networks with PTB

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          Abstract

          Matrin3 is an RNA- and DNA-binding nuclear matrix protein found to be associated with neural and muscular degenerative diseases. A number of possible functions of Matrin3 have been suggested, but no widespread role in RNA metabolism has yet been clearly demonstrated. We identified Matrin3 by its interaction with the second RRM domain of the splicing regulator PTB. Using a combination of RNAi knockdown, transcriptome profiling and iCLIP, we find that Matrin3 is a regulator of hundreds of alternative splicing events, principally acting as a splicing repressor with only a small proportion of targeted events being co-regulated by PTB. In contrast to other splicing regulators, Matrin3 binds to an extended region within repressed exons and flanking introns with no sharply defined peaks. The identification of this clear molecular function of Matrin3 should help to clarify the molecular pathology of ALS and other diseases caused by mutations of Matrin3.

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          R: A Language and Environment for Statistical Computing

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            The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing.

            Both microRNAs and alternative pre-mRNA splicing have been implicated in the development of the nervous system (NS), but functional interactions between these two pathways are poorly understood. We demonstrate that the neuron-specific microRNA miR-124 directly targets PTBP1 (PTB/hnRNP I) mRNA, which encodes a global repressor of alternative pre-mRNA splicing in nonneuronal cells. Among the targets of PTBP1 is a critical cassette exon in the pre-mRNA of PTBP2 (nPTB/brPTB/PTBLP), an NS-enriched PTBP1 homolog. When this exon is skipped, PTBP2 mRNA is subject to nonsense-mediated decay (NMD). During neuronal differentiation, miR-124 reduces PTBP1 levels, leading to the accumulation of correctly spliced PTBP2 mRNA and a dramatic increase in PTBP2 protein. These events culminate in the transition from non-NS to NS-specific alternative splicing patterns. We also present evidence that miR-124 plays a key role in the differentiation of progenitor cells to mature neurons. Thus, miR-124 promotes NS development, at least in part by regulating an intricate network of NS-specific alternative splicing.
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              R: A Lenguage and Environment for Statisctical Computing

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                Author and article information

                Journal
                EMBO J
                EMBO J
                embj
                The EMBO Journal
                John Wiley & Sons, Ltd (Chichester, UK )
                0261-4189
                1460-2075
                04 March 2015
                19 January 2015
                : 34
                : 5
                : 653-668
                Affiliations
                [1 ]Department of Biochemistry, University of Cambridge Cambridge, UK
                [2 ]Department of Molecular Neuroscience, UCL Institute of Neurology London, UK
                [3 ]MRC-Laboratory of Molecular Biology Cambridge, UK
                [4 ]Computational Genomics, Universitat Pompeu Fabra Barcelona, Spain
                [5 ]Catalan Institute for Research and Advanced Studies (ICREA) Barcelona, Spain
                [6 ]INIBIOMA, CONICET-UNComahue Bariloche, Argentina
                Author notes
                * Corresponding author. Tel: +44 1223 333655; E-mail: cwjs1@ 123456cam.ac.uk

                Subject Categories RNA Biology

                [†]

                Present address:Institute of Molecular Biology gGmbH (IMB) Mainz, Germany

                Article
                10.15252/embj.201489852
                4365034
                25599992
                db8d3da7-c035-4771-890c-184c914468f0
                © 2015 The Authors. Published under the terms of the CC BY 4.0 license

                This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Categories
                Articles

                Molecular biology
                alternative splicing,matrin3,ptb
                Molecular biology
                alternative splicing, matrin3, ptb

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