Integrative analysis revealed the molecular mechanism underlying RBM10-mediated splicing regulation

Authors

  • Yongbo Wang,

    1. Laboratory for Novel Sequencing Technology, Functional and Medical Genomics, Berlin Institute for Medical Systems Biology, Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany
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    • These authors contributed equally to this work.
  • Andreas Gogol-Döring,

    1. Laboratory for Novel Sequencing Technology, Functional and Medical Genomics, Berlin Institute for Medical Systems Biology, Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany
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    • These authors contributed equally to this work.
  • Hao Hu,

    1. Max-Planck-Institute for Molecular Genetics, Berlin, Germany
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  • Sebastian Fröhler,

    1. Laboratory for Novel Sequencing Technology, Functional and Medical Genomics, Berlin Institute for Medical Systems Biology, Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany
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  • Yunxia Ma,

    1. Department of Clinical Laboratory, Taiyuan Central Hospital, Taiyuan, Shanxi, P. R. China
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  • Marvin Jens,

    1. Laboratory for Systems Biology of Gene Regulatory Elements, Berlin Institute for Medical Systems Biology, Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany
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  • Jonas Maaskola,

    1. Laboratory for Systems Biology of Gene Regulatory Elements, Berlin Institute for Medical Systems Biology, Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany
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  • Yasuhiro Murakawa,

    1. Laboratory for RNA Biology and Posttranscriptional Regulation, Berlin Institute for Medical Systems Biology, Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany
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  • Claudia Quedenau,

    1. Laboratory for Novel Sequencing Technology, Functional and Medical Genomics, Berlin Institute for Medical Systems Biology, Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany
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  • Markus Landthaler,

    1. Laboratory for RNA Biology and Posttranscriptional Regulation, Berlin Institute for Medical Systems Biology, Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany
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  • Vera Kalscheuer,

    1. Max-Planck-Institute for Molecular Genetics, Berlin, Germany
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  • Dagmar Wieczorek,

    1. Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany
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  • Yang Wang,

    1. Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA
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  • Yuhui Hu,

    Corresponding author
    1. Laboratory for Novel Sequencing Technology, Functional and Medical Genomics, Berlin Institute for Medical Systems Biology, Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany
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  • Wei Chen

    Corresponding author
    1. Laboratory for Novel Sequencing Technology, Functional and Medical Genomics, Berlin Institute for Medical Systems Biology, Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany
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Abstract

RBM10 encodes an RNA binding protein. Mutations in RBM10 are known to cause multiple congenital anomaly syndrome in male humans, the TARP syndrome. However, the molecular function of RBM10 is unknown. Here we used PAR-CLIP to identify thousands of binding sites of RBM10 and observed significant RBM10–RNA interactions in the vicinity of splice sites. Computational analyses of binding sites as well as loss-of-function and gain-of-function experiments provided evidence for the function of RBM10 in regulating exon skipping and suggested an underlying mechanistic model, which could be subsequently validated by minigene experiments. Furthermore, we demonstrated the splicing defects in a patient carrying an RBM10 mutation, which could be explained by disrupted function of RBM10 in splicing regulation. Overall, our study established RBM10 as an important regulator of alternative splicing, presented a mechanistic model for RBM10-mediated splicing regulation and provided a molecular link to understanding a human congenital disorder.

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