HnRNP C binding to inverted Alu elements protects the transcriptome from pre-mRNA circularization

Area of Science:

• Molecular biology
• Cancer research
• RNA biology

Background:

• Back-splicing drives circular RNA (circRNA) biogenesis, but its regulation in tumors is not fully understood.
• Circular RNAs play roles in various biological processes, and their dysregulation is implicated in cancer.
• Group 3 medulloblastoma (MB) is an aggressive pediatric brain tumor with complex molecular underpinnings.

Purpose of the Study:

• To investigate the role of heterogeneous nuclear ribonucleoprotein C (hnRNP C) in regulating circRNA biogenesis in group 3 MB.
• To elucidate the molecular mechanisms by which hnRNP C controls circRNA formation.
• To explore the potential therapeutic implications of targeting hnRNP C in medulloblastoma.

Main Methods:

• Analysis of hnRNP C binding to Alu elements in pre-mRNA.
• Assessment of the impact of hnRNP C expression on circRNA and linear RNA levels.
• Investigation of cytoplasmic double-stranded RNA formation and interferon response.
• In silico and experimental validation of findings in group 3 MB models.

Main Results:

• hnRNP C binds Alu elements to repress circRNA biogenesis in group 3 MB.
• hnRNP C expression levels modulate the balance between linear and circRNA splicing.
• Loss of hnRNP C leads to cytoplasmic double-stranded RNA accumulation and an antiviral response.
• Targeting hnRNP C may enhance cancer surveillance through immune activation.

Conclusions:

• hnRNP C acts as a repressor of circRNA biogenesis, maintaining transcriptome integrity in group 3 MB.
• Dysregulation of hnRNP C contributes to the oncogenic phenotype by altering RNA splicing patterns.
• Targeting hnRNP C presents a potential therapeutic strategy for group 3 MB, possibly by inducing an anti-tumor immune response.