Mutations in the methyl‐CpG‐binding protein 2 (MeCP2) cause Rett syndrome, a severe neurodevelopmental disease associated with ataxia and other post‐natal symptoms similar to autism. Much research interest has focussed on the implications of MeCP2 in disease and neuron physiology. However, little or no attention has been paid to how MeCP2 turnover is regulated. The post‐translational control of MeCP2 is of critical importance, especially as subtle increases or decreases in MeCP2 amounts can affect neuron morphology and (...) function. The latter point is of particular importance for gene therapeutic approaches in which exogenous wild‐type MeCP2 is being introduced into diseased neurons. Further to this, we propose two hypotheses. The first hypothesis discusses the poly‐ubiquitin‐mediated post‐translational regulation of MeCP2 through its two PEST domains. The second hypothesis explores the use of histone deacetylase inhibitors to modulate the amounts of MeCP2 expressed in conjunction with the aforementioned therapeutic approaches. (shrink)

Methyl CpG binding protein 2 (MeCP2) was initially isolated as an exclusive reader of DNA methylated at CpG. This recognition site, was subsequently extended to other DNA methylated residues and it has been the persisting dogma that binding to methylated DNA constitutes its physiologically relevant role. As we review here, two very recent papers fundamentally change our understanding of the interactions of this protein with chromatin, as well as its functional attributes. In the first one, the protein has been (...) shown to bind to tri‐methylated histone H3 (H3K27me3), providing a hint for what might turn out to be the first described chromodomain‐containing protein reader in the animal kingdom, and unequivocally demonstrates the ability of MeCP2 to bind to nonmethylated CpG regions of the genome. The second paper reports how the protein dynamically participates in the formation of constitutive heterochromatin condensates. Histone H3K27me3 is a critical component of this form of chromatin. (shrink)

A recurrent theme in eukaryotic genome regulation stipulates that the properties of DNA are strongly influenced by the nucleoprotein complex into which it is assembled. Methylation of cytosine residues in vertebrate genomes has been implicated in influencing the assembly of locally repressive chromatin architecture. Current models suggest that covalent modification of DNA results in heritable, long‐term transcriptional silencing. In October of 2003, two manuscripts1,2 were published that challenge important aspects of this model, suggesting that modulation of both DNA methylation itself, (...) as well as the machinery implicated in its interpretation, are involved in acute gene regulation. BioEssays 26:217–220, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Rett syndrome (RTT) is an X‐linked dominant neurodevelopmental disorder affecting almost exclusively girls. Although mutations in methyl‐CpG‐binding protein (MeCP2) are known to be associated with RTT, gene expression patterns are not significantly altered in MeCP2‐deficient cells. A recent study1 identified MeCP2‐mediated histone modification and formation of a higher‐order chromatin loop structure specifically associated with silent chromatin at the Dlx5–Dlx6 locus in normal cells, and its absence thereof in RTT patients. This altered expression of Dlx5 through loss of (...) silent chromatin loop formation provides a molecular mechanism underlying RTT and proposes a novel role for MeCP2 in chromatin organization and imprinting. © 2005 Wiley Periodicals, Inc. BioEssays 27:676–680, 2005. © 2005 Wiley Periodicals, Inc. (shrink)