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

Simon Braun1, Mihaela Enculescu1, Samarth T Setty2

  • 1Institute of Molecular Biology (IMB), Ackermannweg 4, 55128, Mainz, Germany.

Nature Communications
|August 19, 2018
PubMed

Insights

Scientists identified over 1000 mutations affecting MST1R (RON) exon 11 splicing, linking them to cancer. They pinpointed heterogeneous nuclear ribonucleoprotein H (HNRNPH) as a key regulator, revealing its role in disease-associated splicing changes.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • Aberrant RNA splicing is a known driver of human diseases, particularly cancer.
  • Understanding the regulatory mechanisms of alternative splicing is crucial for disease intervention.

Purpose of the Study:

  • To investigate the cis-regulatory landscape controlling alternative splicing of MST1R (RON) exon 11.
  • To identify mutations impacting RON exon 11 splicing and their correlation with cancer.
  • To elucidate the role of heterogeneous nuclear ribonucleoprotein H (HNRNPH) in RON splicing.

Main Methods:

  • High-throughput screening of randomly mutated minigenes.
  • Mathematical modeling of splicing kinetics.
  • Integrated analysis of iCLIP and synergy data.
  • Correlation analysis with patient mutation data.

Main Results:

  • Over 1000 mutations affecting RON exon 11 skipping were identified, leading to the pathological RON∆165 isoform.
  • Identified mutations showed a correlation with alternative splicing patterns in cancer patients.
  • Heterogeneous nuclear ribonucleoprotein H (HNRNPH) was identified as a key regulator of RON splicing in both healthy and cancerous tissues.
  • Specific HNRNPH binding sites were pinpointed, and cooperative binding was shown to regulate RON exon 11 splicing.

Conclusions:

  • The study decodes the cis-regulatory landscape of RON exon 11 splicing and its pathological implications in cancer.
  • HNRNPH plays a critical role in regulating RON splicing, offering potential therapeutic targets.
  • Findings provide insights into mutation-driven splicing dysregulation in cancer.

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