The epigenetic role of MeCP2 in gene regualtion

RTT is an X-linked dominant neurodevelopmental disorder caused by mutations in MECP2 (methyl-CpG-binding protein 2). Although a fair amount is known about the biochemical function of MeCP2, the phenotype of Rett syndrome suggests that it plays an unexplored but critical role in the development and maintenance of the nervous system. Earlier studies suggested MeCP2 is a DNA-mediated transcription repressor, however, it is now recognized that it can both activate and repress specific genes, depending on the chromatin context. Still, our knowledge of the set of neuronal MeCP2 target genes is incomplete. In order to understand the molecular basis of MeCP2 functionality, it is necessary to unravel the complex interrelationships between MeCP2 and its genomic targets. We propose to use high-resolution nucleosome ChIP-seq techniques, with integrated genomic and epigenomic approaches, to identify functional genomic targets of MeCP2. In addition, since MeCP2 also binds and modulates chromatin, we will carry out in vitro mechanistic studies to delineate the structural changes elicited on nucleosomes and chromatin by MeCP2. These studies will provide critical knowledge on the functional targets of MeCP2 and the chromatin structures provoked by its presence that regulate gene expression. Such knowledge will be of great benefit in determining both the molecular basis of RTT pathology and potential therapeutic measures.