Suchergebnisse

RNA splicing is widely dysregulated in cancer, frequently due to altered expression or activity of splicing factors (SFs). Microexons are extremely small exons (3–27 nucleotides long) that are highly evolutionarily conserved and play critical roles in promoting neuronal differentiation and development. Inclusion of microexons in mRNA transcripts is mediated by the SF Serine/Arginine Repetitive Matrix 4 (SRRM4), whose expression is largely restricted to neural tissues. However, microexons have been largely overlooked in prior analyses of splicing in cancer, as their small size necessitates specialized computational approaches for their detection. Here, we demonstrate that despite having low expression in normal nonneural tissues, SRRM4 is further silenced in tumors, resulting in the suppression of normal microexon inclusion. Remarkably, SRRM4 is the most consistently silenced SF across all tumor types analyzed, implying a general advantage of microexon down-regulation in cancer independent of its tissue of origin. We show that this silencing is favorable for tumor growth, as decreased SRRM4 expression in tumors is correlated with an increase in mitotic gene expression, and up-regulation of SRRM4 in cancer cell lines dose-dependently inhibits proliferation in vitro and in a mouse xenograft model. Further, this proliferation inhibition is accompanied by induction of neural-like expression and splicing patterns in cancer cells, suggesting that SRRM4 expression shifts the cell state away from proliferation and toward differentiation. We therefore conclude that SRRM4 acts as a proliferation brake, and tumors gain a selective advantage by cutting off this brake. ; This project was funded in part by a grant from the Plan Estatal de Investigación Científica y Técnica y de Innovación to L.S. (PGC2018-101271-B-I00, http://www.ciencia.gob.es). S.A.H. is supported by a Marie Skłodowska-Curie Individual Fellowship from the European Union's Horizon 2020 research and innovation programme (MSCA-IF-2017-794629, http://ec.europa.eu/). X.H. is supported by a PhD fellowship from the Fundación Ramón Areces (http://www.fundacionareces.es). We acknowledge the support of the Spanish Ministry of Economy and Competitiveness, 'Centro de Excelencia Severo Ochoa', the CERCA Programme / Generalitat de Catalunya, and the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) to the EMBL partnership. ; Peer reviewed

The mechanisms by which entire programmes of gene regulation emerged during evolution are poorly understood. Neuronal microexons represent the most conserved class of alternative splicing in vertebrates, and are critical for proper brain development and function. Here, we discover neural microexon programmes in non-vertebrate species and trace their origin to bilaterian ancestors through the emergence of a previously uncharacterized 'enhancer of microexons' (eMIC) protein domain. The eMIC domain originated as an alternative, neural-enriched splice isoform of the pan-eukaryotic Srrm2/SRm300 splicing factor gene, and subsequently became fixed in the vertebrate and neuronal-specific splicing regulator Srrm4/nSR100 and its paralogue Srrm3. Remarkably, the eMIC domain is necessary and sufficient for microexon splicing, and functions by interacting with the earliest components required for exon recognition. The emergence of a novel domain with restricted expression in the nervous system thus resulted in the evolution of splicing programmes that qualitatively expanded the neuronal molecular complexity in bilaterians. ; This work has been funded by the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (ERC-StG-LS2-637591 to M.Ir. and ERC-AdvG-670146 to J.V.), the Spanish Ministry of Economy and Competitiveness (BFU2014-55076-P and BFU2017-89201-P to M.Ir., BFU2014-005153 to J.V., and the 'Centro de Excelencia Severo Ochoa 2013–2017' (SEV-2012-0208)), AGAUR, Fundación Botín (to J.V.) and the Canadian Institutes of Health Research (to B.J.B. and A.-C.G.). RNP mass spectrometric analyses were performed at the CRG/UPF Proteomics Unit (part of ProteoRed-PRB3, supported by PE I+D+i 2013–2016 (PT17/0019) of the ISCIII and ERDF) by 'Programa CERCA Generalitat de Catalunya' and 'Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement' (2017SGR595). A.T.-M. held an FPI-SO fellowship, and Y.M. a Marie Skłodowska-Curie individual fellowship.

Epithelial-mesenchymal interactions are crucial for the development of numerous animal structures. Thus, unraveling how molecular tools are recruited in different lineages to control interplays between these tissues is key to understanding morphogenetic evolution. Here, we study Esrp genes, which regulate extensive splicing programs and are essential for mammalian organogenesis. We find that Esrp homologs have been independently recruited for the development of multiple structures across deuterostomes. Although Esrp is involved in a wide variety of ontogenetic processes, our results suggest ancient roles in non-neural ectoderm and regulating specific mesenchymal-to-epithelial transitions in deuterostome ancestors. However, consistent with the extensive rewiring of Esrp-dependent splicing programs between phyla, most developmental defects observed in vertebrate mutants are related to other types of morphogenetic processes. This is likely connected to the origin of an event in Fgfr, which was recruited as an Esrp target in stem chordates and subsequently co-opted into the development of many novel traits in vertebrates. ; This work has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement No ERC-StG-LS2-637591 to M.I.), the Spanish Ministry of Economy and Competitiveness (grant BFU2014-58908P to J.G.-F, BFU2014-55076-P to M.I., and the 'Centro de Excelencia Severo Ochoa 2013–2017', SEV-2012-0208), and ICREA - Generalitat de Catalunya (Academia Prize to J.G.-F). We acknowledge the support of the CERCA Programme/Generalitat de Catalunya. D.B. held an APIF fellowship from University of Barcelona, Y.M. an EMBO Long Term postdoctoral fellowship (ALTF 1505-2015), C.R. an EMBO long-term fellowship (ALTF 1608-2014), ATM an FPI-SO fellowship. ; Peer reviewed

Epithelial-mesenchymal interactions are crucial for the development of numerous animal structures. Thus, unraveling how molecular tools are recruited in different lineages to control interplays between these tissues is key to understanding morphogenetic evolution. Here, we study Esrp genes, which regulate extensive splicing programs and are essential for mammalian organogenesis. We find that Esrp homologs have been independently recruited for the development of multiple structures across deuterostomes. Although Esrp is involved in a wide variety of ontogenetic processes, our results suggest ancient roles in non-neural ectoderm and regulating specific mesenchymal-to-epithelial transitions in deuterostome ancestors. However, consistent with the extensive rewiring of Esrp-dependent splicing programs between phyla, most developmental defects observed in vertebrate mutants are related to other types of morphogenetic processes. This is likely connected to the origin of an event in Fgfr, which was recruited as an Esrp target in stem chordates and subsequently co-opted into the development of many novel traits in vertebrates. ; This work has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement No ERC-StG-LS2-637591 to M.I.), the Spanish Ministry of Economy and Competitiveness (grant BFU2014-58908P to J.G.-F, BFU2014-55076-P to M.I., and the 'Centro de Excelencia Severo Ochoa 2013-2017', SEV-2012-0208), and ICREA - Generalitat de Catalunya (Academia Prize to J.G.-F). We acknowledge the support of the CERCA Programme/Generalitat de Catalunya. D.B. held an APIF fellowship from University of Barcelona, Y.M. an EMBO Long Term postdoctoral fellowship (ALTF 1505-2015), C.R. an EMBO long-term fellowship (ALTF 1608-2014), ATM an FPI-SO fellowship.