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

Mutations of the MECP2 gene lead to Rett syndrome (RTT), a rare developmental disease causing severe intellectual and physical disability. How the loss or defective function of MeCP2 mediates RTT is still poorly understood. MeCP2 is a global gene expression regulator, acting at transcriptional and post-transcriptional levels. Little attention has been given so far to the contribution of alternative splicing (AS) dysregulation to RTT pathophysiology. To perform a comparative analysis of publicly available RNA sequencing (RNA-seq) studies and generate novel data resources for AS, we explored 100 human datasets and 130 mouse datasets from Mecp2-mutant models, processing data for gene expression and alternative splicing. Our comparative analysis across studies indicates common species-specific differentially expressed genes (DEGs) and differentially alternatively spliced (DAS) genes. Human and mouse dysregulated genes are involved in two main functional categories: cell-extracellular matrix adhesion regulation and synaptic functions, the first category more significantly enriched in human datasets. Our extensive bioinformatics study indicates, for the first time, a significant dysregulation of AS in human RTT datasets, suggesting the crucial contribution of altered RNA processing to the pathophysiology of RTT.