Rett syndrome is a severe neurodevelopmental disorder mainly caused by mutations 
in the transcriptional regulator MeCP2. Although there is no effective therapy 
for Rett syndrome, the recently discovered disease reversibility in mice 
suggests that there are therapeutic possibilities. Identification of MeCP2 
targets or modifiers of the phenotype can facilitate the design of curative 
strategies. To identify possible novel MeCP2 interactors, we exploited a 
bioinformatic approach and selected Ying Yang 1 (YY1) as an interesting 
candidate. We demonstrate that MeCP2 interacts in vitro and in vivo with YY1, a 
ubiquitous zinc-finger epigenetic factor regulating the expression of several 
genes. We show that MeCP2 cooperates with YY1 in repressing the ANT1 gene 
encoding a mitochondrial adenine nucleotide translocase. Importantly, ANT1 mRNA 
levels are increased in human and mouse cell lines devoid of MeCP2, in Rett 
patient fibroblasts and in the brain of Mecp2-null mice. We further demonstrate 
that ANT1 protein levels are upregulated in Mecp2-null mice. Finally, the 
identified MeCP2-YY1 interaction, together with the well-known involvement of 
YY1 in the regulation of D4Z4-associated genes at 4q35, led us to discover the 
anomalous depression of FRG2, a subtelomeric gene of unknown function, in Rett 
fibroblasts. Collectively, our data indicate that mutations in MeCP2 might cause 
the aberrant overexpression of genes located at a specific locus, thus providing 
new candidates for the pathogenesis of Rett syndrome. As both ANT1 mutations and 
overexpression have been associated with human diseases, we consider it highly 
relevant to address the consequences of ANT1 deregulation in Rett syndrome.