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

• Published in: BMC biology Vol. 2; no. 1; p. 21
• Main Authors: Gartler, Stanley M, Varadarajan, Kartik R, Luo, Ping, Canfield, Theresa K, Traynor, Jeff, Francke, Uta, Hansen, R Scott
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 20.09.2004; BioMed Central; BMC
• Subjects: Cells, Cultured; Chromosomes, Human, X - genetics; CpG Islands - genetics; DNA Methylation; Female; Fibroblasts - metabolism; Fibroblasts - pathology; Histones - metabolism; Humans; Immunologic Deficiency Syndromes - genetics; Immunologic Deficiency Syndromes - metabolism; Methyl-CpG-Binding Protein 2 - deficiency; Methyl-CpG-Binding Protein 2 - genetics; Methyl-CpG-Binding Protein 2 - metabolism; Rett Syndrome - genetics; Rett Syndrome - metabolism; Rett Syndrome - pathology; X Chromosome Inactivation
• ISSN: 1741-7007; 1741-7007
• DOI: 10.1186/1741-7007-2-21

In mammals, there is evidence suggesting that methyl-CpG binding proteins may play a significant role in histone modification through their association with modification complexes that can deacetylate and/or methylate nucleosomes in the proximity of methylated DNA. We examined this idea for the X chromosome by studying histone modifications on the X chromosome in normal cells and in cells from patients with ICF syndrome (Immune deficiency, Centromeric region instability, and Facial anomalies syndrome). In normal cells the inactive X has characteristic silencing type histone modification patterns and the CpG islands of genes subject to X inactivation are hypermethylated. In ICF cells, however, genes subject to X inactivation are hypomethylated on the inactive X due to mutations in the DNA methyltransferase (DNMT3B) genes. Therefore, if DNA methylation is upstream of histone modification, the histones on the inactive X in ICF cells should not be modified to a silent form. In addition, we determined whether a specific methyl-CpG binding protein, MeCP2, is necessary for the inactive X histone modification pattern by studying Rett syndrome cells which are deficient in MeCP2 function. 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.