The precise and dynamic modulation of chromatin structure is essential for context-specific transcriptional, or replication-dependent processes. Chromatin alterations resulting from the disruption of such processes are traceable and provide potentially useful disease biomarkers (1
). Mutations in the chromatin-binding protein, methyl–CpG-binding protein 2 (MeCP2), have been linked to the neurodevelopmental disorder Rett syndrome (RTT) and other neurological abnormalities (2
MeCP2 is a member of the methyl–CpG-binding domain (MBD) family of proteins (4
). MeCP2 can bind symmetrically methylated 5′-CpG dinucleotides that are located proximal to at least four A/T nucleotides within the surrounding 11
). This binding is dependent on the recognition of the hydrated methylated CpG by the wedge-shaped MBD (6
Most work characterizing MeCP2 interactions with chromatin has been done with reconstituted templates. Under such conditions, MeCP2 has been shown to bind both methylated and unmethylated templates, with a preference for the former, particularly in the presence of competitor DNA (8
). Under non-physiological ionic conditions, MeCP2 was demonstrated to condense unmethylated chromatin templates (10
). Upon binding to nucleosomes, MeCP2 forms chromatosome-like structures and may even facilitate inter-nucleosomal fiber interactions in vitro
). Early studies indicated that MeCP2 is able to compete with histone H1 for binding linker DNA, and is able to displace ~40% of H1 (12
). In vitro
reconstitution of nucleosomes containing preferential binding sites for MeCP2 indicated that it preferred binding within 10
bp of the dyad axis (8
). By contrast, the interactions of MeCP2 with native chromatin are less extensively characterized.
Much of the early work done on MeCP2 characterized it as a transcriptional repressor due to its association with histone deacetylases (HDACs, HDAC 1 and 2) and SIN3A (4
). As well, MeCP2 was shown to associate with SUV39H1, the histone methyltransferase responsible for methylating lysine 9 of histone H3 (14
), an activity also linked to the DNA methyltransferase, DNMT3A (15
). Furthermore, involvement of MeCP2 in long-range silencing was shown through its ability to form chromatin loops containing the gene Dlx5
). Nevertheless, the perspective began to change with recent publications demonstrating that the majority of MeCP2-bound promoters were positively regulated (17
). MeCP2 has been shown to localize to a broad range of chromatin types, supporting observations of a potential plurality to MeCP2 function (8
). However, besides the requirement for sequence-specificity and DNA methylation, very little is known about the histone determinants [histone variants and post-translational modifications (PTMs)] associated with this multifaceted functionality.
In this paper, we look at the chromatin distribution of MeCP2 in several tissues, and characterize the histone composition variability of nucleosomes with which MeCP2 is associated in the brain.