Decoding a cancer-relevant splicing decision in the RON proto-oncogene using high-throughput mutagenesis

Simon Braun, Mihaela Enculescu, Samarth T. Setty, Mariela Cortés-López, Bernardo P. de Almeida, F. X. Reymond Sutandy, Laura Schulz, Anke Busch, Markus Seiler, Stefanie Ebersberger, Nuno L. Barbosa-Morais, Stefan Legewie (), Julian König () and Kathi Zarnack ()
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Simon Braun: Institute of Molecular Biology (IMB)
Mihaela Enculescu: Institute of Molecular Biology (IMB)
Samarth T. Setty: Goethe University Frankfurt
Mariela Cortés-López: Institute of Molecular Biology (IMB)
Bernardo P. de Almeida: Faculdade de Medicina da Universidade de Lisboa
F. X. Reymond Sutandy: Institute of Molecular Biology (IMB)
Laura Schulz: Institute of Molecular Biology (IMB)
Anke Busch: Institute of Molecular Biology (IMB)
Markus Seiler: Goethe University Frankfurt
Stefanie Ebersberger: Institute of Molecular Biology (IMB)
Nuno L. Barbosa-Morais: Faculdade de Medicina da Universidade de Lisboa
Stefan Legewie: Institute of Molecular Biology (IMB)
Julian König: Institute of Molecular Biology (IMB)
Kathi Zarnack: Goethe University Frankfurt

Nature Communications, 2018, vol. 9, issue 1, 1-18

Abstract: Abstract Mutations causing aberrant splicing are frequently implicated in human diseases including cancer. Here, we establish a high-throughput screen of randomly mutated minigenes to decode the cis-regulatory landscape that determines alternative splicing of exon 11 in the proto-oncogene MST1R (RON). Mathematical modelling of splicing kinetics enables us to identify more than 1000 mutations affecting RON exon 11 skipping, which corresponds to the pathological isoform RON∆165. Importantly, the effects correlate with RON alternative splicing in cancer patients bearing the same mutations. Moreover, we highlight heterogeneous nuclear ribonucleoprotein H (HNRNPH) as a key regulator of RON splicing in healthy tissues and cancer. Using iCLIP and synergy analysis, we pinpoint the functionally most relevant HNRNPH binding sites and demonstrate how cooperative HNRNPH binding facilitates a splicing switch of RON exon 11. Our results thereby offer insights into splicing regulation and the impact of mutations on alternative splicing in cancer.

Date: 2018
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DOI: 10.1038/s41467-018-05748-7

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