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


RESULTS
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.


CONCLUSIONS
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.
Gartler
Stanley M
SM
Department of Medicine, University of Washington, Seattle, WA, USA. gartler@genetics.washington.edu
Varadarajan
Kartik R
KR
Luo
Ping
P
Canfield
Theresa K
TK
Traynor
Jeff
J
Francke
Uta
U
Hansen
R Scott
RS
D002478:Cells, Cultured; D041321:Chromosomes, Human, X / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000378:metabolism; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D015518:Rett Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D049951:X Chromosome Inactivation
D006657:Histones; C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2