Integrative analyses of transcriptome and DNA methylome from human neurons expressing multiple MECP2 levels

Rett Syndrome (RTT) is a monogenic disorder, which mainly affects girls and is caused by mutations in methyl-CpG- binding protein 2 (MECP2). It is characterized by symptoms like loss of speech, breathing abnormalities, seizures and autistic behaviour. MeCP2, which is abundantly expressed in mature neurons, binds methylated cytosines in genomic DNA and is thought to function as a transcriptional regulator. It has been suggested to play an important role in a variety of cellular processes like transcriptional regulation, alternative splicing, maintenance of global structure of chromatin, and protein synthesis. Despite extensive research to understand how MeCP2 functions, the exact role of this protein is ambiguous. To address this, we have generated in vitro human neurons with multiple levels of MeCP2 expression and performed whole-genome bisulfite sequencing (WGBS) and mRNA sequencing. We also performed Assay for Transposase-Accessible Chromatin (ATAC-Seq) in order to gain insight into the role of MeCP2 on chromatin accessibility and nucleosome positioning. We developed an interactive tool to explore and study the relationship between different types of omics data. By integrative analyses of methylation and gene expression datasets, we find that genes with higher gene body methylation are more likely to be down-regulated in MeCP2 overexpressing neurons and up-regulated in MeCP2 knockout neurons. This suggests that gene expression inversely correlates with MeCP2 expression and gene body methylation levels, suggesting a transcriptional repressor role for MeCP2.