In-depth analysis of the RNA editing landscape in intracranial aneurysms and its potential role in alternative splicing.

Abstract

Intracranial aneurysm (IA) is a focal localized dilation of cerebral arteries and is a life-threatening cerebrovascular disease. Emerging evidences have emphasized the significance of post-transcriptional regulation in diseases, particularly through the two most critical regulatory layers of RNA editing (RE) and alternative splicing (AS). However, the interplay between these mechanisms and their impact on IA pathophysiology remains unclear. This study integrated multi-cohort datasets to establish a comprehensive landscape of RE in IAs. We observed a marked decrease in RNA editing levels during the transition from unruptured to ruptured aneurysms. Further analysis revealed a dual mechanism of AS by RE: direct modulation of AS via edits near splice sites that alter regulatory sequences, and indirect influence through changes in the binding affinity and specificity of RNA-binding proteins (RBPs). By constructing an RES-RBP-AS regulatory network, we identified key nodes potentially involved in IA progression via RE-mediated splicing regulation. These findings not only provide new insights into IA molecular mechanisms, but also lay a theoretical foundation for the developing therapies strategies targeting post-transcriptional regulation.