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.