title: The impact of MECP2 mutations in the expression patterns of Rett syndrome patients.
abstract: Rett syndrome (RTT), the second most common cause of mental retardation in females, has been associated with mutations in MeCP2, the archetypical member of the methyl-CpG binding domain (MBD) family of proteins. MeCP2 additionally possesses a transcriptional repression domain (TRD). We have compared the gene expression profiles of RTT- and normal female-derived lymphoblastoid cells by using cDNA microarrays. Clustering analysis allowed the classification of RTT patients according to the localization of the MeCP2 mutation (MBD or TRD) and those with clinically diagnosed RTT but without detectable MeCP2 mutations. Numerous genes were observed to be overexpressed in RTT patients compared with control samples, including excellent candidate genes for neurodevelopmental disease. Chromatin immunoprecipitation analysis confirmed that binding of MeCP2 to corresponding promoter CpG islands was lost in RTT-derived cells harboring a mutation in the region of the MECP2 gene encoding the MBD. Bisulfite genomic sequencing demonstrated that the majority of MeCP2 binding occurred in DNA sequences with methylation-associated silencing. Most importantly, the finding that these genes are also methylated and bound by MeCP2 in neuron-related cells suggests a role in this neurodevelopmental disease. Our results provide new data of the underlying mechanisms of RTT and unveil novel targets of MeCP2-mediated gene repression.
authors.affiliation: Cancer Epigenetics Laboratory, Molecular Pathology Programme, Spanish National Cancer Centre, Melchor Fernández Almagro 3, 28029 Madrid, Spain.
authors.forename: Esteban
authors.initials: E
authors.lastname: Ballestar
authors.forename: Santiago
authors.initials: S
authors.lastname: Ropero
authors.forename: Miguel
authors.initials: M
authors.lastname: Alaminos
authors.forename: Judith
authors.initials: J
authors.lastname: Armstrong
authors.forename: Fernando
authors.initials: F
authors.lastname: Setien
authors.forename: Ruben
authors.initials: R
authors.lastname: Agrelo
authors.forename: Mario F
authors.initials: MF
authors.lastname: Fraga
authors.forename: Michel
authors.initials: M
authors.lastname: Herranz
authors.forename: Sonia
authors.initials: S
authors.lastname: Avila
authors.forename: Mercedes
authors.initials: M
authors.lastname: Pineda
authors.forename: Eugenia
authors.initials: E
authors.lastname: Monros
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
mesh_terms: D015153:Blotting, Western; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2; D009154:Mutation; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D015518:Rett Syndrome / Q000235:genetics* / Q000378:metabolism
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D012097:Repressor Proteins