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Alternative splicing changes are frequently observed in cancer and are starting to be recognized as important signatures for tumor progression and therapy. However, their functional impact and relevance to tumorigenesis remain mostly unknown. We carried out a systematic analysis to characterize the potential functional consequences of alternative splicing changes in thousands of tumor samples. This analysis revealed that a subset of alternative splicing changes affect protein domain families that are frequently mutated in tumors and potentially disrupt protein-protein interactions in cancer-related pathways. Moreover, there was a negative correlation between the number of these alternative splicing changes in a sample and the number of somatic mutations in drivers. We propose that a subset of the alternative splicing changes observed in tumors may represent independent oncogenic processes that could be relevant to explain the functional transformations in cancer, and some of them could potentially be considered alternative splicing drivers (AS drivers). ; H.C.-G. and E.E. were supported by the MINECO and FEDER (BIO2014-52566-R), Consolider RNAREG (CSD2009-00080), AGAUR (SGR2014-1121), the European ITN Network RNP-Net (ID: 289007), and the Sandra Ibarra Foundation for Cancer (FSI2013). E.P.-P. and A.G. were supported by the SBP CC grant (P30 CA030199). All authors thank The Cancer Genome Atlas project for making their data publicly available. The Computational RNA Biology Group is part of the Research Programme on Biomedical Informatics (GRIB), which is a member of ELIXIR-Excelerate of the European Union Horizon 2020 Programme 2014-2020 (No. 676559) and of the Spanish National Bioinformatics Institute (INB), PRB2-ISCIII and is supported by grant PT13/0001/0023 of the PE I+D+I 2013-2016, funded by ISCIII and FEDER. ; Peer Reviewed ; Postprint (published version)

Alternative splicing changes are frequently observed in cancer and are starting to be recognized as important signatures for tumor progression and therapy. However, their functional impact and relevance to tumorigenesis remain mostly unknown. We carried out a systematic analysis to characterize the potential functional consequences of alternative splicing changes in thousands of tumor samples. This analysis revealed that a subset of alternative splicing changes affect protein domain families that are frequently mutated in tumors and potentially disrupt protein-protein interactions in cancer-related pathways. Moreover, there was a negative correlation between the number of these alternative splicing changes in a sample and the number of somatic mutations in drivers. We propose that a subset of the alternative splicing changes observed in tumors may represent independent oncogenic processes that could be relevant to explain the functional transformations in cancer, and some of them could potentially be considered alternative splicing drivers (AS drivers). ; H.C.-G. and E.E. were supported by the MINECO and FEDER (BIO2014-52566-R), Consolider RNAREG (CSD2009-00080), AGAUR (SGR2014-1121), the European ITN Network RNP-Net (ID: 289007), and the Sandra Ibarra Foundation for Cancer (FSI2013). E.P.-P. and A.G. were supported by the SBP CC grant (P30 CA030199). All authors thank The Cancer Genome Atlas project for making their data publicly available. The Computational RNA Biology Group is part of the Research Programme on Biomedical Informatics (GRIB), which is a member of ELIXIR-Excelerate of the European Union Horizon 2020 Programme 2014-2020 (No. 676559) and of the Spanish National Bioinformatics Institute (INB), PRB2-ISCIII and is supported by grant PT13/0001/0023 of the PE I+D+I 2013-2016, funded by ISCIII and FEDER. ; Peer Reviewed ; Postprint (published version)

© The Author(s). 2019. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. ; We describe ReorientExpress, a method to perform reference-free orientation of transcriptomic long sequencing reads. ReorientExpress uses deep learning to correctly predict the orientation of the majority of reads, and in particular when trained on a closely related species or in combination with read clustering. ReorientExpress enables long-read transcriptomics in non-model organisms and samples without a genome reference without using additional technologies and is available at https://github.com/comprna/reorientexpress ; Part of this work was funded by the Spanish Government and FEDER with grants BIO2017-85364-R and MDM-2014-0370 and by Catalan Government (AGAUR) with grant SGR2017-1020. JI was supported by a PhD grant from FCT (Fundação para a Ciência e a Tecnologia) Portugal. IdlR had funding from an FPI grant from the Spanish Government (PRE2018-083413). ; info:eu-repo/semantics/publishedVersion

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. ; We thank Nejc Haberman (UCL) for assisting in the generation of the splicing maps and preparation of the iCLIP data. This work was supported by Wellcome Trust programme grants to CWJS (077877 and 092900), and by grants to EE and NB BIO2011-23920 and RNAREG (CSD2009-00080) from the Spanish Government and by the Sandra Ibarra Foundation for Cancer (FSI2013). JA was supported by a Boehringer Ingelheim Fonds studentship. ; This is the final version of the article. It first appeared from EMBO Press/Wiley via http://dx.doi.org/10.15252/embj.201489852

RNA structure plays a fundamental role in internal initiation of translation. Picornavirus internal ribosome entry site (IRES) are long, efficient cis-acting elements that recruit the ribosome to internal mRNA sites. However, little is known about long-range constraints determining the IRES RNA structure. Here, we sought to investigate the functional and structural relevance of the invariant apical stem of a picornavirus IRES. Mutation of this apical stem revealed better performance of G:C compared with C:G base pairs, demonstrating that the secondary structure solely is not sufficient for IRES function. In turn, mutations designed to disrupt the stem abolished IRES activity. Lack of tolerance to accept genetic variability in the apical stem was supported by the presence of coupled covariations within the adjacent stem-loops. SHAPE structural analysis, gel mobility-shift and microarrays-based RNA accessibility revealed that the apical stem contributes to maintain IRES RNA structure through the generation of distant interactions between two adjacent stem-loops. Our results demonstrate that a highly interactive structure constrained by distant interactions involving invariant G:C base pairs plays a key role in maintaining the RNA conformation necessary for IRES-mediated translation. © The Author(s) 2011. Published by Oxford University Press. ; Ministerio de Ciencia e Innovación (BFU2008-02159, CSD2009-00080 to E.M.S.); Institutional grant from Fundació n Ramón Areces. Work at Universitat Pompeu Fabra was supported by grant BIO2008-01091. Work at Centro de Astrobiología was supported by grants BIO2007-67523, BIO2010-20696, EUI2008-00158; CSIC (grant 200920I040); European Union and Comunidad de Madrid. CIBERehd is funded by the Instituto de Salud Carlos III. Funding for open access charge: CSD-2009-0080, BFU2008-0 ; Peer Reviewed

Acknowledgements: We thank the Interfant treatment protocol and local physicians for contributing patient samples: Dr. Ronald W Stam (Princess Maxima Centre, Utrech), Dr. Mireia Camos and Dr. Jose Luis Fuster (Spanish Society of Pediatric Hematoncology), Dr. Paola Ballerini (A. Trousseau Hospital, Paris). We also thank Prof. Paresh Vyas (Oxford Univeristy, UK) and Prof. Kajsa Paulsson (Lund University, Sweden) for facilitating access to their RNA-seq database. This work has been supported by the European Research Council (CoG-2014-646903, PoC-2018-811220) to PM, the Spanish Ministry of Economy and Competitiveness (MINECO, SAF-SAF2016-80481-R, BIO2017-85364-R) to PM and EE, the Generalitat de Catalunya (SGR330, SGR102 and PERIS) to PM and EE, the Spanish Association against cancer (AECC-CI-2015) to CB, and the Health Institute Carlos III (ISCIII/FEDER, PI14-01191) to CB. PM also acknowledges financial support from the Obra Social La Caixa-Fundaciò Josep Carreras. SRZ and TV are supported by a Marie Curie fellowships. OM is supported by the Catalan Government through a Beatriu de Pinos fellowship. MB is supported by MINECO through a PhD scholarship. PM is an investigator of the Spanish Cell Therapy cooperative network (TERCEL).