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

  • 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.
Metadaten
Author:Simon Braun, Mihaela Enculescu, Samarth T. Setty, Mariela Cortés-López, Bernardo Pinto de Almeida, F. X. Reymond Sutandy, Laura Schulz, Anke Busch, Markus Seiler, Stefanie Ebersberger, Nuno L. Barbosa-Morais, Stefan Legewie, Julian König, Katharina ZarnackORCiDGND
URN:urn:nbn:de:hebis:30:3-464766
DOI:https://doi.org/10.1038/s41467-018-05748-7
ISSN:2041-1723
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/30120239
Parent Title (English):Nature Communications
Publisher:Nature Publishing Group UK
Place of publication:[London]
Document Type:Article
Language:English
Year of Completion:2018
Date of first Publication:2018/08/17
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2018/08/30
Tag:Alternative splicing; Cancer genomics; Computational models; High-throughput screening
Volume:9
Issue:1, Art. 3315
Page Number:18
First Page:1
Last Page:18
Note:
Rights and permissions: Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.
HeBIS-PPN:451010280
Institutes:Exzellenzcluster / Exzellenzcluster Makromolekulare Komplexe
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0