Journal Article

DKFZ-2025-01812

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Deep indel mutagenesis reveals the regulatory and modulatory architecture of alternative exon splicing.

Baeza-Centurión, P. (First author)DKFZ* ; Miñana, B. ; Faure, A. J. ; Thompson, M. ; Bonnal, S. ; Quarantani, G. ; Clarke, J. ; Lehner, B. ; Valcárcel, J.

2025
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41467-025-62957-7

Abstract: 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.

Keyword(s): Exons: genetics (MeSH) ; Humans (MeSH) ; Alternative Splicing: genetics (MeSH) ; INDEL Mutation: genetics (MeSH) ; Oligonucleotides, Antisense: genetics (MeSH) ; Mutagenesis (MeSH) ; Deep Learning (MeSH) ; RNA Precursors: genetics (MeSH) ; Oligonucleotides, Antisense ; RNA Precursors

Note: Pablo Baeza-Centurión

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Contributing Institute(s):

1. Bibliothek (W510)

Research Program(s):

1. 319H - Addenda (POF4-319H) (POF4-319H)

Appears in the scientific report 2025

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