Integrated gene expression and alternative splicing analysis in human and mouse models of Rett syndrome

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Mutations in the MECP2 gene cause Rett syndrome (RTT), a severe neurodevelopmental disorder.
• The precise mechanisms by which MECP2 dysfunction leads to RTT remain unclear.
• The role of alternative splicing (AS) dysregulation in RTT pathophysiology has been largely unexplored.

Purpose of the Study:

• To investigate the contribution of alternative splicing (AS) to Rett syndrome (RTT) pathophysiology.
• To perform a comparative bioinformatics analysis of gene expression and AS in human and mouse RTT models.

Main Methods:

• Comparative analysis of 100 human and 130 mouse RNA sequencing datasets from Mecp2-mutant models.
• Bioinformatic processing to identify differentially expressed genes (DEGs) and differentially alternatively spliced (DAS) genes.
• Functional enrichment analysis of dysregulated genes.

Main Results:

• Identified common species-specific DEGs and DAS genes between human and mouse RTT models.
• Dysregulated genes are primarily involved in cell-extracellular matrix adhesion and synaptic functions.
• Significant AS dysregulation was observed in human RTT datasets, with cell-extracellular matrix adhesion being a prominent affected category.

Conclusions:

• Alternative splicing (AS) is significantly dysregulated in human Rett syndrome (RTT) datasets.
• Altered RNA processing, specifically AS, plays a crucial role in RTT pathophysiology.
• This study provides novel data resources and insights into the molecular mechanisms underlying RTT.