Rett syndrome (RTT) is a complex neurodevelopmental disorder that has been associated with mutations of methyl-CpG binding protein 2 (MeCP2). MeCP2 acts as a transcriptional repressor and binds to histone modifier proteins, which prompted us to wonder whether MeCP2 disruption affects global histone modification patterns. Taking a two-fold approach of using high-performance capillary electrophoresis (HPCE) and western blot, we analyzed the acetylation and methylation status of histones H3 and H4 in a mouse model of RTT where the MeCP2 locus is genetically disrupted. The comparison of cortex, midbrain and cerebellum in wild-type and MeCP2-knock out mice did not reveal any significant difference in the global H3 and H4 histone modification patterns. Our results suggest that MeCP2 deficiency involves local and gene-specific chromatin changes rather than massive histone modification changes.