Integrated analysis of human transcriptome data for Rett syndrome finds a network of involved genes

Rett syndrome (RTT) is a rare disorder causing severe intellectual and physical disability. The cause is a mutation in the gene coding for the methyl-CpG binding protein 2 (MECP2), a multifunctional regulator protein. Purpose of the study was integration and investigation of multiple gene expression profiles in human cells with impaired MECP2 gene to obtain a robust, data-driven insight in molecular disease mechanisms. Information about changed gene expression was extracted from five previously published studies, integrated and the resulting differentially expressed genes were analysed using overrepresentation analysis of biological pathways and gene ontology, and network analysis. We identified a set of genes, which are significantly changed not in all but several transcriptomics datasets and were not mentioned in the context of RTT before. We found that these genes are involved in several processes and molecular pathways known to be affected in RTT. Integrating transcription factors we identified a possible link how MECP2 regulates cytoskeleton organisation via MEF2C and CAPG. Integrative analysis of omics data and prior knowledge databases is a powerful approach to identify links between mutation and phenotype especially in rare disease research where little data is available.雷特综合征（Rett syndrome, RTT）是一种罕见的致残性疾病，可导致严重的智力与肢体残疾。其致病根源为编码甲基CpG结合蛋白2（methyl-CpG binding protein 2, MECP2）的基因发生突变，该蛋白属于多功能调控蛋白。本研究旨在整合并分析MECP2基因功能受损的人类细胞中的多组基因表达谱，以获得关于该疾病分子发病机制的稳健且基于数据的深入洞察。研究人员从五项已发表的既往研究中提取差异基因表达相关信息，完成整合后，通过生物通路富集分析、基因本体（Gene Ontology, GO）富集分析以及网络分析，对所得差异表达基因进行了系统解析。本研究鉴定出一组基因：它们并非在所有转录组数据集中均出现显著表达变化，但却在既往与RTT相关的研究中从未被提及；同时发现这些基因参与了若干已知受RTT影响的生物学过程与分子通路。进一步整合转录因子相关数据后，我们揭示了MECP2可能通过MEF2C与CAPG调控细胞骨架组织的潜在关联。整合组学数据与先验知识数据库的分析方法，是揭示突变与表型之间关联的有效手段，尤其适用于数据匮乏的罕见病研究领域。