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@ARTICLE{BaezaCenturin:304271,
      author       = {P. Baeza-Centurión$^*$ and B. Miñana and A. J. Faure and
                      M. Thompson and S. Bonnal and G. Quarantani and J. Clarke
                      and B. Lehner and J. Valcárcel},
      title        = {{D}eep indel mutagenesis reveals the regulatory and
                      modulatory architecture of alternative exon splicing.},
      journal      = {Nature Communications},
      volume       = {16},
      number       = {1},
      issn         = {2041-1723},
      address      = {[London]},
      publisher    = {Springer Nature},
      reportid     = {DKFZ-2025-01812},
      pages        = {8117},
      year         = {2025},
      note         = {Pablo Baeza-Centurión},
      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.},
      keywords     = {Exons: genetics / Humans / Alternative Splicing: genetics /
                      INDEL Mutation: genetics / Oligonucleotides, Antisense:
                      genetics / Mutagenesis / Deep Learning / RNA Precursors:
                      genetics / Oligonucleotides, Antisense (NLM Chemicals) / RNA
                      Precursors (NLM Chemicals)},
      cin          = {W510},
      ddc          = {500},
      cid          = {I:(DE-He78)W510-20160331},
      pnm          = {319H - Addenda (POF4-319H)},
      pid          = {G:(DE-HGF)POF4-319H},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40885722},
      doi          = {10.1038/s41467-025-62957-7},
      url          = {https://inrepo02.dkfz.de/record/304271},
}