Abstract
BackgroundRett syndrome is a neurodevelopmental and autistic disease caused by mutations of Methyl-CpG-binding protein 2 (MECP2) gene. MeCP2 protein is mainly expressed in neurons and binds to methylated gene promoters to suppress their expression, indicating that Rett syndrome is caused by the deregulation of target genes in neurons. However, it is likely that there are more unidentified neuronal MeCP2-targets associated with the neurological features of RTT.ResultsUsing a genome-microarray approach, we found 22 genomic regions that contain sites potentially regulated by MeCP2 based on the features of MeCP2 binding, DNA methylation, and repressive histone modification in human cell lines. Within these regions, Chromatin immunoprecipitation (ChIP) analysis revealed that MeCP2 binds to the upstream regions of the protocadherin genes PCDHB1 and PCDH7 in human neuroblastoma SH-SY5Y cells. PCDHB1 and PCDH7 promoter activities were down-regulated by MeCP2, but not by MBD-deleted MeCP2. These gene expression were up-regulated following MeCP2 reduction with siRNA in SH-SY5Y cells and in the brains of Mecp2-null mice. Furthermore, PCDHB1 was up-regulated in postmortem brains from Rett syndrome patients.ConclusionsWe identified MeCP2 target genes that encode neuronal adhesion molecules using ChIP-on-BAC array approach. Since these protocadherin genes are generally essential for brain development, aberrant regulation of these molecules may contribute to the pathogenesis of the neurological features observed in Rett syndrome.
Highlights
Rett syndrome is a neurodevelopmental and autistic disease caused by mutations of Methyl-CpGbinding protein 2 (MECP2) gene
Methyl-CpG-binding protein 2 (MeCP2) is one of the proteins associated with epigenetic regulation, and mutations of this gene have been identified in the majority of patients with a severe neurodevelopmental disorder, Rett syndrome (RTT), characterized by seizures, ataxic gait, language dysfunction, and autistic behavior [1,2]
We screened Bacterial artificial chromosomes (BACs) clones encompassing hypermethylation site(s) and repressive histone modification sites based on DNA methylation using the based methylated CpG island amplification (BAMCA) and Chromatin immunoprecipitation (ChIP)-on-BAC array assay with an anti-histone H3K9-2Me antibody in the same cell lines [19,20]
Summary
Rett syndrome is a neurodevelopmental and autistic disease caused by mutations of Methyl-CpGbinding protein 2 (MECP2) gene. Its deficiency does not result in the significant deregulation of the expression of a subset of genes as determined by a comparative expression microarray analyses between Mecp2-null mice and wild-type mice [8], but induces global changes in neuronal chromatin structure [9]. These findings indicate that MeCP2 may be a global gene silencer. It is still worthwhile to identify MeCP2-target genes which that are centrally involved in RTT pathogenesis, since MeCP2 functions cell-autonomously in neuronal maturation and dendritic arborization and discrete subsets of genes regulated by MeCP2 may be essential for mature neuronal function [11]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
