Comprehensive transcriptome analysis of cerebral cavernous malformation across multiple species and genotypes

Area of Science:

• Genomics
• Molecular Biology
• Pathobiology

Background:

• Cerebral cavernous malformation (CCM) is a vascular disorder with poorly understood molecular mechanisms.
• Transcriptomic analysis offers a powerful approach to identify key genes and pathways involved in disease pathogenesis.

Purpose of the Study:

• To identify critical genes, functions, and molecular networks contributing to CCM pathobiology.
• To compare transcriptomic data across multiple species and disease genotypes for conserved mechanisms.
• To establish a comprehensive transcriptome library for CCM research.

Main Methods:

• RNA sequencing of laser microdissected neurovascular units from human CCM lesions and control tissues.
• Transcriptomic analysis of mouse brain microvascular endothelial cells and Caenorhabditis elegans models with induced Ccm gene loss.
• Differential gene expression analysis, cross-species gene annotation, network analysis, and Gene Ontology (GO) enrichment analysis.

Main Results:

• Hundreds of differentially expressed genes (DEGs) were identified in each model.
• A common gene set and the GO term 'establishment of organelle localization' (GO:0051656) were conserved across species and genotypes.
• Twenty-four GO functions related to cell-to-cell adhesion, neutrophil-mediated immunity, ion transport, and oxidative stress responses were identified in multiple models.

Conclusions:

• This study provides a cross-species transcriptomic resource for CCM research.
• Conserved pathways, including organelle localization, cell adhesion, and immune responses, are implicated in CCM pathobiology.
• The findings facilitate hypothesis generation and mechanistic studies for CCM development and potential therapeutic targets.