Normal histone modifications on the inactive X chromosome in ICF and Rett syndrome cells: implications for methyl-CpG binding proteins

We show here that the inactive X in ICF cells, which appears to be hypomethylated at all CpG islands, exhibits normal histone modification patterns. In addition, in Rett cells with no functional MeCP2 methyl-CpG binding protein, the inactive X also exhibits normal histone modification patterns.These data suggest that DNA methylation and the associated methyl-DNA binding proteins may not play a critical role in determining histone modification patterns on the mammalian inactive X chromosome at the sites analyzed.Although it has been known for some time that histone modifications play a role in gene expression [1], it is only in the last several years that the details of these modifications have been more fully described. Acetylation and methylation of histone tails, for example, exhibit characteristic patterns for expressed and repressed genes in all eukaryotes studied [2]. This generality of histone modification and gene expression holds for eukaryotes with and without DNA methylation, indicating that DNA methylation is not required for histone modification. In organisms with DNA methylation, however, interactions between histone modification and DNA methylation do appear to exist.In Neurospora, histone methylation appears to determine DNA methylation patterns [3,4]. In Arabidopsis, non-CpG DNA methylation also appears to be determined by histone methyltransferases, whereas CpG methylation does not [5,6]. In mammals, there is considerable evidence suggesting that methyl-CpG binding proteins may play a significant role in histone modification through their association with histone deacetylases [7-11]. Mutations in the MeCP2 methyl-DNA binding protein, which are the cause of most Rett syndrome cases [12], support this model, because human male and female cells with MECP2 mutations exhibit histone hyperacetylation [10]. Histone hyperacetylation was also observed in mice with Mecp2 mutations [13]. Thus, DNA methylation is upstream of histone modification in this model o