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Functional Impact and Regulation of Alternative Splicing in Mouse Heart Development and Disease

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Abstract

Alternative splicing (AS) plays a major role in the generation of transcript diversity. In the heart, roles have been described for some AS variants, but the global impact and regulation of AS patterns are poorly understood. Here, we studied the AS profiles in heart disease, their relationship with heart development, and the regulatory mechanisms controlling AS dynamics in the mouse heart. We found that AS profiles characterized the different groups and that AS and gene expression changes affected independent genes and biological functions. Moreover, AS changes, specifically in heart disease, were associated with potential protein–protein interaction changes. While developmental transitions were mainly driven by the upregulation of MBNL1, AS changes in disease were driven by a complex regulatory network, where PTBP1 played a central role. Indeed, PTBP1 over-expression was sufficient to induce cardiac hypertrophy and diastolic dysfunction, potentially by perturbing AS patterns.

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Acknowledgements

We would like to thank CNIC Genomics and Bioinformatics Units for technical support and scientific discussion. We particularly thank Fernando Martínez for his help solving numerous technical problems that arose during the development of this study. Finally, we would like to thank Simon Bartlett for his careful writing review of the manuscript.

Funding

This study was supported by grants from the European Union [CardioNeT-ITN-289600 and CardioNext-608027 to E.L-P.], the Spanish Ministry of Economy and Competitiveness [SAF2015-65722-R and SAF2012-31451 to E.L-P.], the Science, Innovation and Universities (MCIU) [RTI2018-102084-B-I00 to F.S.C], the Carlos III Institute of Health [CPII14/00027 to E.L-P. and RD012/0042/0066 to P.G-P. and E.L-P.], and the Madrid Regional Government [2010-BMD-2321 “Fibroteam” to E.L-P.]. The study also received support from the Plan Estatal de I + D + I 2013–2016 – European Regional Development Fund (ERDF) “A way of making Europe,” Spain. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN), and the Pro CNIC Foundation.

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Authors and Affiliations

  1. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain

    Carlos Martí-Gómez, Javier Larrasa-Alonso, Marina López-Olañeta, María Villalba-Orero, Pablo García-Pavía, Fátima Sánchez-Cabo & Enrique Lara-Pezzi

  2. Centro de Investigación Biomédica en Red Cardiovascular (CIBERCV), Madrid, Spain

    María Villalba-Orero, Pablo García-Pavía & Enrique Lara-Pezzi

  3. Facultad de Veterinaria, Universidad Complutense de Madrid, Madrid, Spain

    María Villalba-Orero

  4. Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain

    Pablo García-Pavía

  5. Facultad de Ciencias de La Salud, Universidad Francisco de Vitoria, UFV, Pozuelo de Alarcón, Madrid, Spain

    Pablo García-Pavía

  6. Bioinformatics Unit, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernandez Almagro, 3, 28029, Madrid, Spain

    Fátima Sánchez-Cabo

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  1. Carlos Martí-Gómez
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  2. Javier Larrasa-Alonso
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  6. Fátima Sánchez-Cabo
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  7. Enrique Lara-Pezzi
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Correspondence to Fátima Sánchez-Cabo or Enrique Lara-Pezzi.

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All animal experiments were approved by the Ethics Committee for Animal Welfare of the CNIC and by the Regional Government of Madrid (PROEX 332–15, PROEX 177–17). No human studies were carried out by the authors of this article.

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Martí-Gómez, C., Larrasa-Alonso, J., López-Olañeta, M. et al. Functional Impact and Regulation of Alternative Splicing in Mouse Heart Development and Disease. J. of Cardiovasc. Trans. Res. 15, 1239–1255 (2022). https://doi.org/10.1007/s12265-022-10244-x

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