Venkata Jonnakuti, BS: No financial relationships to disclose
Introduction: Meningiomas, the most common type of primary brain tumors, are genetically heterogenous tumors. Although most meningiomas are benign, a subpopulation is aggressive with high risk of recurrence. Furthermore, while we have previously demonstrated that gene expression differences define three biological meningioma subtypes, the underlying causative mechanisms are yet to be fully understood. A better understanding of meningioma oncogenesis may lead to the identification of new diagnostic and therapeutic targets. One mechanism that could lead to differential gene expression is alternative polyadenylation (APA). APA is a post-transcriptional mechanism that produces differential 3’UTR mRNA isoforms -- directly influencing the interaction of the mRNA with miRNAs and RNA-binding proteins and modulating mRNA stability. While APA has been shown to alter the expression of oncogenes and tumor suppressors in other cancers, its prevalence in meningiomas has yet to be elucidated.
Methods: We developed a novel computational tool to explore APA dynamics from RNA-seq data, using (1) an attention-based ML model that infers the underlying “grammar” to accurately detect APA sites; (2) Poly(A)-capped read detection that takes advantage of underlying sequencing biochemistry to ensure tissue specificity of differential APA usage; and (3) vector projections that effectively calculate APA dynamics.
Results: We report differential expression of several core APA factors, implicating dysregulated APA in meningiomas. Our analysis of APA dynamics across benign and malignant meningioma conditions demonstrates 446 significant genes differentially regulated by APA. Notably, we identified a tumor suppressor that not only inhibits cell growth and induces apoptosis but also interacts with tumor suppressor p53 and p300, as a gene undergoing significant 3’UTR lengthening.
Conclusion : Our analytical framework could be generalized to APA-centric disease investigations. Our results suggest a novel APA-driven aspect in meningiomas that could elucidate the underlying molecular interplay of malignant meningiomas. Further mechanistic investigation is needed to better understand the role of APA in meningioma.
