Mecp2-null mice provide new neuronal targets for Rett syndrome.
BACKGROUND
Rett syndrome (RTT) is a complex neurological disorder that is one of the most frequent causes of mental retardation in women. A great landmark in research in this field was the discovery of a relationship between the disease and the presence of mutations in the gene that codes for the methyl-CpG binding protein 2 (MeCP2). Currently, MeCP2 is thought to act as a transcriptional repressor that couples DNA methylation and transcriptional silencing. The present study aimed to identify new target genes regulated by Mecp2 in a mouse model of RTT.


RESULTS
We have compared the gene expression profiles of wild type (WT) and Mecp2-null (KO) mice in three regions of the brain (cortex, midbrain, and cerebellum) by using cDNA microarrays. The results obtained were confirmed by quantitative real-time PCR. Subsequent chromatin immunoprecipitation assays revealed seven direct target genes of Mecp2 bound in vivo (Fkbp5, Mobp, Plagl1, Ddc, Mllt2h, Eya2, and S100a9), and three overexpressed genes due to an indirect effect of a lack of Mecp2 (Irak1, Prodh and Dlk1). The regions bound by Mecp2 were always methylated, suggesting the involvement of the methyl-CpG binding domain of the protein in the mechanism of interaction.


CONCLUSIONS
We identified new genes that are overexpressed in Mecp2-KO mice and are excellent candidate genes for involvement in various features of the neurological disease. Our results demonstrate new targets of MeCP2 and provide us with a better understanding of the underlying mechanisms of RTT.
Urdinguio
Rocio G
RG
Cancer Epigenetics Laboratory, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Lopez-Serra
Lidia
L
Lopez-Nieva
Pilar
P
Alaminos
Miguel
M
Diaz-Uriarte
Ramon
R
Fernandez
Agustin F
AF
Esteller
Manel
M
D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation; D005260:Female; D015870:Gene Expression; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D015518:Rett Syndrome / Q000235:genetics* / Q000378:metabolism
D051783:Methyl-CpG-Binding Protein 2