A Systematic Identification of RNA-Binding Proteins (RBPs) Driving Aberrant Splicing in Cancer

Area of Science:

• Molecular Biology
• Bioinformatics
• Genomics

Background:

• Alternative splicing (AS) generates diverse mRNA variants from a single gene.
• RNA-binding proteins (RBPs) are key regulators of AS and implicated in cancer.
• CLIP-seq identifies RBP binding sites, aiding splicing change analysis.

Purpose of the Study:

• To develop and validate an algorithm for detecting RBPs associated with differential splicing.
• To refine existing methods for predicting splicing events and RBP enrichment.
• To investigate RBP roles in various cancer types using large-scale genomic data.

Main Methods:

• Integrated multiple CLIP-seq databases with a differential splicing detection algorithm.
• Developed a novel algorithm for RBP-splicing association analysis.
• Applied the algorithm to knockdown experiments and The Cancer Genome Atlas (TCGA) and TARGET cancer datasets.

Main Results:

• The algorithm accurately predicts statistically significant RBPs based on splicing alterations.
• Identified novel associations between RBPs (e.g., CREBBP, MBNL2) and multiple cancer types.
• The refined method is integrated into the Bioconductor package EventPointer 3.14.

Conclusions:

• The algorithm improves the prediction of RBP-driven splicing changes.
• Provides novel insights into RBP involvement in cancer biology.
• Highlights RBPs as potential therapeutic targets for cancer treatment.