Gioiosa Silvia, Gasparini Silvia, Presutti Carlo, Rinaldi Arianna, Castrignanò Tiziana, Mannironi Cecilia
CINECA, SuperComputing Applications and Innovation Department, Via dei Tizii 6, 00185, Rome, Italy.
Institute of Molecular Biology and Pathology, National Research Council, 00185, Rome, Italy.
Sci Rep. 2025 Jan 22;15(1):2778. doi: 10.1038/s41598-025-86114-8.
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.
MECP2基因突变会导致雷特综合征（RTT），这是一种罕见的发育性疾病，会导致严重的智力和身体残疾。目前对于MeCP2功能丧失或缺陷如何介导雷特综合征仍知之甚少。MeCP2是一种全局基因表达调节因子，在转录和转录后水平发挥作用。到目前为止，可变剪接（AS）失调对雷特综合征病理生理学的影响很少受到关注。为了对公开可用的RNA测序（RNA-seq）研究进行比较分析并生成可变剪接的新数据资源，我们探索了来自Mecp2突变模型的100个人类数据集和130个小鼠数据集，对基因表达和可变剪接数据进行处理。我们对各项研究的比较分析表明存在常见的物种特异性差异表达基因（DEG）和差异可变剪接（DAS）基因。人类和小鼠的失调基因涉及两个主要功能类别：细胞-细胞外基质粘附调节和突触功能，第一类在人类数据集中富集程度更高。我们广泛的生物信息学研究首次表明，人类雷特综合征数据集中可变剪接存在显著失调，提示RNA加工改变对雷特综合征病理生理学具有关键作用。
