MECP2/Mecp2 gene expression is known to be regulated by regulatory elements (REs) within the promoter and a silencer element within the Mecp2 intron 1 [12,13,18] (Figure 1B). Implying the role of DNA methylation in MECP2 regulation, reduced MECP2 expression in the brains of male autistic patients correlates with human MECP2 promoter hypermethylation [2,19]. Moreover, reduced Mecp2 expression in the postnatal murine brain in response to early maternal separation and stress is associated with hypermethylation of the mouse Mecp2 promoter [20]. However, possible differential impact of DNA methylation on MECP2/Mecp2 isoforms is currently unknown. DNA methylation is a major epigenetic modification that controls gene expression without affecting the underlying DNA sequences (reviewed in [21,22]). DNA methylation at the cytosine residues (5-methylcytosine (5mC)) of the CpG dinucleotides is carried out by DNA methyltransferases (DNMT) and is generally considered to be a repressive epigenetic modification [1,23]. Conversely, 5-hydroxymethylcytosine (5hmC), which is generated by oxidation of 5mC by TET proteins is generally considered to be an active epigenetic mark [24,25]. Promoter methylation is mostly associated with gene silencing [26], while DNA methylation at both intronic and exonic regions are shown to correlate with isoform-specific transcription by alternative splicing or by utilizing alternate promoters [27,28].
