Quantitative analysis questions the role of MeCP2 as a global regulator of alternative splicing.

Rett Syndrome (RTT) is a devastating neurological disorder affecting approximately 1 in 10,000 female births. Most cases of RTT are caused by mutations in the gene identified as methyl-CG binding protein 2 (MECP2) which is an epigenetic reader of DNA methylation. Although the primary function of MeCP2 is to recruit NCoR to methylated sites in the genome, the downstream effect on gene expression is subtle and multiple additional functions have been proposed. Here we focus on the influence of MeCP2 on one of these: alternative splicing to generate different messenger RNAs from a single primary transcript. Using machine learning approaches, we show that neither MeCP2 nor DNA methylation influence alternative splicing. Our results emphasize the importance of multi-variate quantitative analyses and they challenge the over-interpretation of causal relationships based on high-throughput data sets.