Modulator-Dependent RBPs Changes Alternative Splicing Outcomes in Kidney Cancer

Area of Science:

• Molecular Biology
• Genomics
• Bioinformatics

Background:

• Alternative splicing is crucial in human disease.
• RNA-binding proteins (RBPs) regulate alternative splicing.
• Genetic and epigenetic factors modulate RBP activity.

Purpose of the Study:

• Investigate the role of 'modulator' genes in altering RBP splicing regulation.
• Comprehensively analyze RBP-mediated splicing interactions and their modulators.
• Explore the functional implications of these interactions in kidney cancer.

Main Methods:

• Developed a computational framework to identify modulator-mediated RBP-splicing interactions.
• Utilized TCGA-KIRC RNA sequencing data.
• Defined modulator function categories based on expression correlation with splicing outcomes.
• Performed pathway enrichment analysis on identified targets.

Main Results:

• Identified over 1 million modulator-mediated RBP-splicing interactions involving 137 RBPs, 4,309 splicing events, and 2,905 modulators.
• Focused on QKI, an RBP influencing numerous splicing events, identifying 2,014 changing triplets.
• QKI splicing targets are enriched in pathways critical for cancer, including tight junction, endocytosis, and MAPK signaling.

Conclusions:

• This study provides the first comprehensive analysis of how alternative splicing changes relate to protein expression levels under the same RBP regulation.
• Findings offer a novel perspective on alternative splicing mechanisms in kidney cancer.
• Identified modulator-RBP-splicing networks may serve as potential targets for therapeutic interventions.