Widespread 3' UTR splicing regulates expression of oncogene transcripts through multiple mechanisms

Area of Science:

• Transcriptomics
• Molecular Biology
• Cancer Genomics

Background:

• Splicing in 3' untranslated regions (3' UTRs) typically triggers degradation via nonsense-mediated decay (NMD) due to exon junction complex (EJC) presence.
• However, 3' UTR introns (3UIs) are prevalent in normal tissues and cancers, suggesting alternative regulatory roles.

Purpose of the Study:

• To investigate the prevalence and function of 3UI-containing transcripts across diverse cancer types.
• To determine if 3UI splicing is NMD-sensitizing or acts as a regulatory mechanism.
• To explore the role of 3UI splicing in cancer, particularly in relation to signaling pathways.

Main Methods:

• Transcriptome assembly from The Cancer Genome Atlas (TCGA) data (7897 solid tumour and normal samples).
• Analysis of 3UI-containing transcript expression and correlation with NMD factors (e.g., UPF1).
• Identification of bona-fide 3UIs and assessment of their NMD-sensitizing potential.
• Investigation of 3UI splicing in colon cancer and enrichment analysis with signaling pathways (e.g., Wnt).

Main Results:

• Thousands of 3UI-containing transcripts were identified, many expressed across multiple cancers.
• Bona-fide 3UIs are not predominantly NMD-sensitizing and can rescue transcripts from degradation.
• 3UI transcripts are frequently over-spliced in cancer samples.
• In colon cancer, 3UI splicing is enriched in the Wnt signaling pathway, notably affecting CTNNB1 expression.

Conclusions:

• 3' UTR splicing is a widespread phenomenon, not a rare event.
• 3UI splicing offers regulatory mechanisms for transcript expression, potentially independent of EJC.
• Dysregulation of 3UI splicing, particularly in cancer, impacts key signaling pathways like Wnt, offering new insights into cancer biology.