Juan Valcárcel

Institució Catalana de Recerca i Estudis Avançats

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Sophie Bonnal

Centre for Genomic Regulation

Belén Miñana

Centre for Genomic Regulation

Panagiotis Papasaikas

Friedrich Miescher Institute

Claudia Vivori

The Francis Crick Institute

Concepción Martínez

Sylvester Comprehensive Cancer Center

Michael Sattler

Technical University of Munich

Eduardo Eyras

Australian National University

Fátima Gebauer

Centre for Genomic Regulation

Juan Ortı́n

Consejo Superior de Investigaciones Científicas

Luisa Vigevani

Centre for Genomic Regulation

Cooperative Institutions

Centre for Genomic Regulation

Pompeu Fabra University

Consejo Superior de Investigaciones Científicas

European Molecular Biology Laboratory

Instituto de Salud Carlos III

Barcelona Institute for Science and Technology

Centre National de la Recherche Scientifique

European Molecular Biology Laboratory

Universitat de Barcelona

Howard Hughes Medical Institute

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Towards the understanding of the mechanisms responsible for alternative splicing modulation by mild heat shock

HAL (Le Centre pour la Communication Scientifique Directe) (2017)

Christelle Aigueperse Valentin Vautrot Luisa Vigevani Papasaikas Panegiotis Nathalie Nicot

Modulation (music)

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Changes of SF3B1 phosphorylation status participate to alternative splicing modulation by mild heat shock

HAL (Le Centre pour la Communication Scientifique Directe) (2018)

Christelle Aigueperse Valentin Vautrot Luisa Vigevani Papasaikas Panegiotis Nathalie Nicot

Modulation (music)

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Interaction of U2AF ⁶⁵ RS Region with Pre-mRNA of Branch Point and Promotion Base Pairing with U2 snRNA

Science (1996)

Juan Valcárcel Rajesh Gaur Ravinder Singh Michael R. Green

The mammalian splicing factor U2AF 65 binds to the polypyrimidine tract adjacent to the 3′ splice site and promotes assembly of U2 small nuclear ribonucleoprotein on the upstream branch point, an interaction that involves base pairing with U2 small nuclear RNA (snRNA). U2AF 65 contains an RNA binding domain, required for interaction with the polypyrimidine tract, and an arginine-serine-rich (RS) region, required for U2 snRNP recruitment and splicing. Here it is reported that binding of U2AF 65 to the polypyrimidine tract directed the RS domain to contact the branch point and promoted U2 snRNA-branch point base pairing even in the absence of other splicing factors. Analysis of RS domain mutants indicated that the ability of U2AF 65 to contact the branch point, to promote the U2 snRNA-branch point interaction, and to support splicing are related activities, requiring only a few basic amino acids. Thus, the U2AF 65 RS domain plays a direct role in modulating spliceosomal RNA-RNA interactions.

snRNP

Small nuclear RNA

Polypyrimidine tract

Prp24

Small nuclear ribonucleoprotein

Splicing factor

10.1126/science.273.5282.1706

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Citations (280)

Inhibition of msl-2 splicing by Sex-lethal reveals interaction between U2AF35 and the 3′ splice site AG

Nature (1999)

Livia Merendino Sabine Guth Daniel Bilbao Concepción Martínez Juan Valcárcel

Polypyrimidine tract

Spliceosome

Splicing factor

10.1038/45602

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Citations (291)

Mutations primarily alter the inclusion of alternatively spliced exons

bioRxiv (Cold Spring Harbor Laboratory) (2020)

Pablo Baeza-Centurion Belén Miñana Juan Valcárcel Ben Lehner

Abstract Genetic analyses and systematic mutagenesis have revealed that synonymous, non-synonymous and intronic mutations frequently alter the inclusion levels of alternatively spliced exons, consistent with the concept that altered splicing might be a common mechanism by which mutations cause disease. However, most exons expressed in any cell are highly-included in mature mRNAs. Here, by performing deep mutagenesis of highly-included exons and by analysing the association between genome sequence variation and exon inclusion across the transcriptome, we report that mutations only very rarely alter the inclusion of highly-included exons. This is true for both exonic and intronic mutations as well as for perturbations in trans . Therefore, mutations that affect splicing are not evenly distributed across primary transcripts but are focussed in and around alternatively spliced exons with intermediate inclusion levels. These results provide a resource for prioritising synonymous and other variants as disease-causing mutations.

Exonic splicing enhancer

Exon trapping

10.1101/2020.06.30.181404

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Citations (1)

Faculty Opinions recommendation of SRp20 is a proto-oncogene critical for cell proliferation and tumor induction and maintenance.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature (2011)

Juan Valcárcel Sophie Bonnal

10.3410/f.9484956.10128057

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The hnRNP A1 protein regulates HIV-1 tat splicing via a novel intron silencer element

The EMBO Journal (2001)

Thomas Ø Tange Christian Kroun Damgaard Sabine Guth Juan Valcárcel Jørgen Kjems

snRNP

Minigene

Exonic splicing enhancer

Protein splicing

SR protein

Heterogeneous nuclear ribonucleoprotein

Heterogeneous ribonucleoprotein particle

10.1093/emboj/20.20.5748

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Citations (167)

Faculty Opinions recommendation of Distinct properties of the XY pseudoautosomal region crucial for male meiosis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature (2011)

Juan Valcárcel Maria Paola Paronetto

Meiosis requires that each chromosome find its homologous partner and undergo at least one crossover. X-Y chromosome segregation hinges on efficient crossing-over in a very small region of homology, the pseudoautosomal region (PAR). We find that mouse PAR DNA occupies unusually long chromosome axes, potentially as shorter chromatin loops, predicted to promote double-strand break (DSB) formation. Most PARs show delayed appearance of RAD51/DMC1 foci, which mark DSB ends, and all PARs undergo delayed DSB-mediated homologous pairing. Analysis of Spo11β isoform-specific transgenic mice revealed that late RAD51/DMC1 foci in the PAR are genetically distinct from both early PAR foci and global foci and that late PAR foci promote efficient X-Y pairing, recombination, and male fertility. Our findings uncover specific mechanisms that surmount the unique challenges of X-Y recombination. PMID: 21330546 Funding information This work was supported by: NICHD NIH HHS, United States Grant ID: R01 HD040916-10 NICHD NIH HHS, United States Grant ID: R01 HD040916-01 NICHD NIH HHS, United States Grant ID: R01 HD040916

Pseudoautosomal region

10.3410/f.9463958.10113055

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Differential 3′ splice site recognition of SMN1 and SMN2 transcripts by U2AF and U2 snRNP

RNA (2009)

Mafalda Martins de Araújo Sophie Bonnal Michelle L. Hastings Adrian R. Krainer Juan Valcárcel

Spinal Muscular atrophy is a prevalent genetic disease caused by mutation of the SMN1 gene, which encodes the SMN protein involved in assembly of small nuclear ribonucleoprotein (snRNP) complexes. A paralog of the gene, SMN2 , cannot provide adequate levels of functional SMN because exon 7 is skipped in a significant fraction of the mature transcripts. A C to T transition located at position 6 of exon 7 is critical for the difference in exon skipping between SMN1 and SMN2 . Here we report that this nucleotide difference results in increased ultraviolet light-mediated crosslinking of the splicing factor U2AF 65 with the 3′ splice site of SMN1 intron 6 in HeLa nuclear extract. U2 snRNP association, analyzed by native gel electrophoresis, is also more efficient on SMN1 than on SMN2 , particularly under conditions of competition, suggesting more effective use of limiting factors. Two trans -acting factors implicated in SMN regulation, SF2/ASF and hnRNP A1, promote and repress, respectively, U2 snRNP recruitment to both RNAs. Interestingly, depending on the transcript and the regulatory factor, the effects on U2 binding not always correlate with changes in U2AF 65 crosslinking. Furthermore, blocking recognition of a Tra2-β1-dependent splicing enhancer located in exon 7 inhibits U2 snRNP recruitment without affecting U2AF 65 crosslinking. Collectively, the results suggest that both U2AF binding and other steps of U2 snRNP recruitment can be control points in SMN splicing regulation.

snRNP

SMN1

Small nuclear ribonucleoprotein

Splicing factor

Exonic splicing enhancer

10.1261/rna.1273209

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Citations (40)

Reconstruction of composite regulator-target splicing networks from high-throughput transcriptome data

BMC Genomics (2015)

Panagiotis Papasaikas Arvind Rao Peter Huggins Juan Valcárcel A. Javier Lopez

We present a computational framework tailored for the modeling of the complex, dynamic relationships that are encountered in splicing regulation. The starting point is whole-genome transcriptomic data from high-throughput array or sequencing methods that are used to quantify gene expression and alternative splicing across multiple contexts. This information is used as input for state of the art methods for Graphical Model Selection in order to recover the structure of a composite network that simultaneously models exon co-regulation and their cognate regulators. Community structure detection and social network analysis methods are used to identify distinct modules and key actors within the network. As a proof of concept for our framework we studied the splicing regulatory network for Drosophila development using the publicly available modENCODE data. The final model offers a comprehensive view of the splicing circuitry that underlies fly development. Identified modules are associated with major developmental hallmarks including maternally loaded RNAs, onset of zygotic gene expression, transitions between life stages and sex differentiation. Within-module key actors include well-known developmental-specific splicing regulators from the literature while additional factors previously unassociated with developmental-specific splicing are also highlighted. Finally we analyze an extensive battery of Splicing Factor knock-down transcriptome data and demonstrate that our approach captures true regulatory relationships.

Gene regulatory network

10.1186/1471-2164-16-s10-s7

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Citations (19)