title: Chromatin context and ncRNA highlight targets of MeCP2 in brain.
abstract: The discovery that Rett syndrome (RTT) is caused by mutation of the methyl-CpG-binding-protein MeCP2 provided a major breakthrough in understanding the neurodevelopmental disorder and accelerated MeCP2 research. However, gene regulation by MeCP2 is complicated. The current consensus for MeCP2 remains as a classical repressor complex, with major emphasis on its role in methylation-dependent binding and repression. However, recent evidence indicates additional regulatory roles, suggesting non-classical mechanisms in gene activation. This has opened the field of MeCP2 research and suggests that the gene targets may not be the usual suspects, that is, dependent only on DNA methylation. Here we examine how chromatin binding and sequence preference may confer MeCP2 functionality, and connect relevant pathways in an active genome. Finding both genomic and proteomic evidence to indicate MeCP2 spliceosome interaction, we consequently discovered broad MeCP2 enrichment of the transcriptome while our focus toward long non-coding RNA (lncRNA) revealed MeCP2 association with RNCR3. Our data may indicate an as-yet-unappreciated role between lncRNA and MeCP2. We hypothesize that ncRNA may mediate chromatin-remodeling events by interacting with MeCP2, thereby conferring changes in gene expression. We consider that these results may suggest new mechanisms of gene regulation conferred by MeCP2 and its interactions upon chromatin structure and gene function.
authors.affiliation: Epigenetics in Human Health and Disease Laboratory; Baker IDI Heart and Diabetes Institute; The Alfred Medical Research and Education Precinct; Melbourne, VIC, Australia.
authors.forename: Scott S
authors.initials: SS
authors.lastname: Maxwell
authors.affiliation: Embryology Unit; Children's Medical Research Institute; Sydney, NSW, Australia.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Pelka
authors.affiliation: Embryology Unit; Children's Medical Research Institute; Sydney, NSW, Australia; Sydney Medical School; University of Sydney; Sydney, NSW, Australia.
authors.forename: Patrick Pl
authors.initials: PP
authors.lastname: Tam
authors.affiliation: Epigenetics in Human Health and Disease Laboratory; Baker IDI Heart and Diabetes Institute; The Alfred Medical Research and Education Precinct; Melbourne, VIC, Australia; Epigenomic Profiling Facility; Baker IDI Heart and Diabetes Institute; The Alfred Medical Research and Education Precinct; Melbourne, VIC, Australia; Department of Pathology; The University of Melbourne; Parkville, VIC, Australia; Faculty of Medicine, Nursing and Health Sciences; Monash University; VIC, Australia.
authors.forename: Assam
authors.initials: A
authors.lastname: El-Osta
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism*; D018899:CpG Islands; D019175:DNA Methylation; D005786:Gene Expression Regulation; D016678:Genome; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020543:Proteome; D062085:RNA, Long Noncoding / Q000378:metabolism*; D017381:Spliceosomes / Q000378:metabolism*
chemical_list: D002843:Chromatin; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D020543:Proteome; D062085:RNA, Long Noncoding
keywords: DNA methylation; MeCP2; chromatin; gene expression; ncRNA; spliceosome