Abstract
MeCP2 is an abundant protein in mature nerve cells, where it binds to DNA sequences containing methylated cytosine. Mutations in the MECP2 gene cause the severe neurological disorder Rett syndrome (RTT), provoking intensive study of the underlying molecular mechanisms. Multiple functions have been proposed, one of which involves a regulatory role in splicing. Here we leverage the recent availability of high-quality transcriptomic data sets to probe quantitatively the potential influence of MeCP2 on alternative splicing. Using a variety of machine learning approaches that can capture both linear and non-linear associations, we show that widely different levels of MeCP2 have a minimal effect on alternative splicing in three different systems. Alternative splicing was also apparently indifferent to developmental changes in DNA methylation levels. Our results suggest that regulation of splicing is not a major function of MeCP2. They also highlight the importance of multi-variate quantitative analyses in the formulation of biological hypotheses.
Highlights
MeCP2 is an important mediator of epigenetic regulation in mammalian cells, and in neurons [1,2,3]
Most cases of Rett syndrome (RTT) are caused by mutations in the gene identified as methyl-CG binding protein 2 (MECP2) which is an epigenetic reader of DNA methylation
We focus on the influence of MeCP2 on one of these: alternative splicing to generate different messenger RNAs from a single primary transcript
Summary
MeCP2 (methyl CpG binding protein 2) is an important mediator of epigenetic regulation in mammalian cells, and in neurons [1,2,3]. MeCP2 is a chromatin protein that binds to modified cytosine residues, primarily mCG [5], the most abundant modification in mammalian genomes, and mCA, mCAC [6], which is a feature of neuronal cells [7, 8] This association with chromatin enables MeCP2 to interpret epigenetic signals to modulate gene expression events. Other roles for MeCP2 have been hypothesised, including chromatin compaction, micro-RNA processing, and regulation of alternative splicing (reviewed in reference [12]) These hypotheses highlight alternative roles of MeCP2 in orchestrating gene expression at transcriptional and post-transcriptional levels, but they have varying degrees of support from data
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