Methyl-CpG-binding protein 2 (MeCP2) is an X-linked transcription factor that binds to methylated CpG dinucleotides in the genome. Its primary function was originally thought to be limited to repression of gene transcription in keeping with the transcriptional silence of methylated genes. CpG methylation is a hallmark of epigenetic regulation of genome function because it is copied to replicating DNA strands during cell division and is maintained across development as a form of epigenetic memory. Cytosine methylation in CpG clusters (islands) in the genome can modify chromatin structure by inhibiting activator DNA-binding proteins from binding to recognition sequences in DNA while allowing access by repressor proteins to methyl-CpP binding domains (MBD) that prevent the activation of gene transcription. MeCP2 is a member of the MBD family of proteins that associate with histone deacetylases (HDACs) and histone metyltransferases (HMTs) to form stable repressor complexes. MeCP2 point mutations cause Rett syndrome, the most common inherited form of mental retardation in girls. However, exactly which protein partners are affected by different MeCP2 mutations is controversial. For example, MeCP2 has been shown to associate with the Sin3a–HDAC chromatin remodeling complex in the brain-derived neurotrophic factor (Bdnf) gene to modulate its expression, and loss of MeCP2 from the Bdnf promoter causes loss of local histone methylation (Chen et al, 2003; Martinowich et al, 2003). However, the function of MeCP2 may be determined by its multifaceted interactions with many different protein partners leading to different functional outcomes. Indeed, MeCP2 appears to associate with many different complexes in brain nuclear extracts some of which repress, but others, like CREB, activate, gene transcription (Chahrour et al, 2008).

An alternative interpretation of MeCP2's function in the brain is that it alters the global chromatin state of neurons and regulates transcriptional noise in a manner that depends on the methylation state of DNA (Skene et al, 2010) and the activation state of MeCP2. MeCP2 is regulated differentially by phosphorylation at several serine sites. Calcium calmodulin kinase-dependent phosphorylation at S421 releases MeCP2 from the Bdnf promoter and facilitates its transcription (Zhou et al, 2006). With regard to drugs of abuse, manipulations of MeCP2 levels in the nucleus accumbens (Nac) alter drug-induced conditioned place preference (Deng et al, 2010) and manipulations in the dorsal striatum alter escalation of cocaine intake (Im et al, 2010). Further, amphetamine (AMPH) selectively increases p-Ser421-MeCP2 in the prelimbic cortex (PLC) and in GAD67-positive GABA/parvalbumin-positive interneurons in the NAc in a D1 receptor-dependent manner (Deng et al, 2010). This expression pattern differs markedly from AMPH-induced immediate early gene or phospho-CREB induction.

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