Deep indel mutagenesis reveals the regulatory and modulatory architecture of alternative exon splicing

While altered pre-mRNA splicing is a frequent mechanism by which genetic variants cause disease, the regulatory architecture of human exons remains poorly understood. Antisense oligonucleotides (AONs) that target pre-mRNA splicing have been approved as therapeutics for various pathologies including...

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Autores: Baeza Centurión, Pablo, 1989-, Miñana Gómez, Belén, Faure, Andre J., Thompson, Mike, Bonnal, Sophie, Quarantani, Gioia, Clarke, Joseph, Lehner, Ben, 1978-, Valcárcel, J. (Juan)
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/71517
Acceso en línea:http://hdl.handle.net/10230/71517
http://dx.doi.org/10.1038/s41467-025-62957-7
Access Level:acceso abierto
Palabra clave:Genetics
RNA splicing
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dc.title.none.fl_str_mv Deep indel mutagenesis reveals the regulatory and modulatory architecture of alternative exon splicing
title Deep indel mutagenesis reveals the regulatory and modulatory architecture of alternative exon splicing
spellingShingle Deep indel mutagenesis reveals the regulatory and modulatory architecture of alternative exon splicing
Baeza Centurión, Pablo, 1989-
Genetics
RNA splicing
title_short Deep indel mutagenesis reveals the regulatory and modulatory architecture of alternative exon splicing
title_full Deep indel mutagenesis reveals the regulatory and modulatory architecture of alternative exon splicing
title_fullStr Deep indel mutagenesis reveals the regulatory and modulatory architecture of alternative exon splicing
title_full_unstemmed Deep indel mutagenesis reveals the regulatory and modulatory architecture of alternative exon splicing
title_sort Deep indel mutagenesis reveals the regulatory and modulatory architecture of alternative exon splicing
dc.creator.none.fl_str_mv Baeza Centurión, Pablo, 1989-
Miñana Gómez, Belén
Faure, Andre J.
Thompson, Mike
Bonnal, Sophie
Quarantani, Gioia
Clarke, Joseph
Lehner, Ben, 1978-
Valcárcel, J. (Juan)
author Baeza Centurión, Pablo, 1989-
author_facet Baeza Centurión, Pablo, 1989-
Miñana Gómez, Belén
Faure, Andre J.
Thompson, Mike
Bonnal, Sophie
Quarantani, Gioia
Clarke, Joseph
Lehner, Ben, 1978-
Valcárcel, J. (Juan)
author_role author
author2 Miñana Gómez, Belén
Faure, Andre J.
Thompson, Mike
Bonnal, Sophie
Quarantani, Gioia
Clarke, Joseph
Lehner, Ben, 1978-
Valcárcel, J. (Juan)
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Genetics
RNA splicing
topic Genetics
RNA splicing
description While altered pre-mRNA splicing is a frequent mechanism by which genetic variants cause disease, the regulatory architecture of human exons remains poorly understood. Antisense oligonucleotides (AONs) that target pre-mRNA splicing have been approved as therapeutics for various pathologies including patient-customised treatments for rare diseases, but AON discovery is currently slow and expensive, limiting the wider adoption of the approach. Here we show that deep indel mutagenesis (DIM) -which can be made experimentally at very low cost - provides an efficient strategy to chart the regulatory landscape of human exons and rapidly identify candidate splicing-modulating oligonucleotides. DIM reveals autonomous effects of insertions, while systematic deletion scans delineate the checkerboard architecture of sequential enhancers and silencers in a model alternative exon. The results also suggest a mechanism for repression of transmembrane domain-encoding exons and for the generation of microexons. Leveraging deep learning tools, we provide a resource, DANGO, that predicts the splicing regulatory landscape of all human exons and can help to identify effective splicing-modulating antisense oligonucleotides.
publishDate 2025
dc.date.none.fl_str_mv 2025
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/71517
http://dx.doi.org/10.1038/s41467-025-62957-7
url http://hdl.handle.net/10230/71517
http://dx.doi.org/10.1038/s41467-025-62957-7
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Nature communications. 2025 Aug 30;16(1):8117
info:eu-repo/grantAgreement/EC/H2020/670146
info:eu-repo/grantAgreement/EC/H2020/883742
info:eu-repo/grantAgreement/EC/HE/101071936
info:eu-repo/grantAgreement/ES/2PE/PID2020-114630GB-I00
info:eu-repo/grantAgreement/ES/3PE/PRE2022-102744
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature Research
publisher.none.fl_str_mv Nature Research
dc.source.none.fl_str_mv reponame:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
reponame_str Repositorio Digital de la UPF
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spelling Deep indel mutagenesis reveals the regulatory and modulatory architecture of alternative exon splicingBaeza Centurión, Pablo, 1989-Miñana Gómez, BelénFaure, Andre J.Thompson, MikeBonnal, SophieQuarantani, GioiaClarke, JosephLehner, Ben, 1978-Valcárcel, J. (Juan)GeneticsRNA splicingWhile altered pre-mRNA splicing is a frequent mechanism by which genetic variants cause disease, the regulatory architecture of human exons remains poorly understood. Antisense oligonucleotides (AONs) that target pre-mRNA splicing have been approved as therapeutics for various pathologies including patient-customised treatments for rare diseases, but AON discovery is currently slow and expensive, limiting the wider adoption of the approach. Here we show that deep indel mutagenesis (DIM) -which can be made experimentally at very low cost - provides an efficient strategy to chart the regulatory landscape of human exons and rapidly identify candidate splicing-modulating oligonucleotides. DIM reveals autonomous effects of insertions, while systematic deletion scans delineate the checkerboard architecture of sequential enhancers and silencers in a model alternative exon. The results also suggest a mechanism for repression of transmembrane domain-encoding exons and for the generation of microexons. Leveraging deep learning tools, we provide a resource, DANGO, that predicts the splicing regulatory landscape of all human exons and can help to identify effective splicing-modulating antisense oligonucleotides.This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreements 670146 and 883742) and from the European Union's Horizon Europe under the grant agreement No 101071936. We also acknowledge support of the Spanish Ministry of Science and Innovation through the Centro de Excelencia Severo Ochoa (CEX2020-001049-S, MCIN/AEI/10.13039/501100011033), and the Generalitat de Catalunya through the CERCA programme. We are grateful to the CRG Core Technologies Programme for their support and assistance in this work. We received funding from the Spanish State Research Agency (PID2020-114630GB-I00/AEI/10.13039/501100011033), LCF/PR/HR21/52410004, EMBL Partnership, the Bettencourt Schueller Foundation, the AXA Research Fund, and Agencia de Gestio d’Ajuts Universitaris i de Recerca (AGAUR, 2017 SGR 1322). GQ was supported by PRE2022-102744, financed by MCIN/AEI/10.13039/501100011033 and FSE + . J.C. is funded by the BBSRC DTP (Bio-technology and Biological Sciences Research Council, Biosciences Doctoral Training Programme, Cambridge, UK. The Genotype-Tissue Expression (GTEx) data used for the analyses described in this manu-script were obtained from the GTEx Portal on May 8, 2018 and dbGaP accession number phs000424.v7.p2 on May 8, 2018. The GTEx Project was supported by the Common Fund of the Office of the Director of the NIH and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Funded by the European Union. Views and opinions expressed are, however, those of the author(s) only and do not necessarily reflect those of the European Union. Neither the European Union nor the granting authority can be held responsible for them.Nature Research202520252025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/71517http://dx.doi.org/10.1038/s41467-025-62957-7reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésNature communications. 2025 Aug 30;16(1):8117info:eu-repo/grantAgreement/EC/H2020/670146info:eu-repo/grantAgreement/EC/H2020/883742info:eu-repo/grantAgreement/EC/HE/101071936info:eu-repo/grantAgreement/ES/2PE/PID2020-114630GB-I00info:eu-repo/grantAgreement/ES/3PE/PRE2022-102744© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.http://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/715172026-06-12T07:21:37Z
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