Nature Genetics 37, 1274 - 1279 (2005)
Published online: 23 October 2005; | doi:10.1038/ng1663
Global hypomethylation of the genome in XX embryonic stem cellsIlona Zvetkova1, 5, 6, Anwyn Apedaile1, 6, Bernard Ramsahoye2, Jacqueline E Mermoud1, Lucy A Crompton1, Rosalind John3, Robert Feil4
& Neil Brockdorff11
MRC Clinical Sciences Centre, ICFM, Hammersmith Hospital, DuCane Road, London, W12 ONN, UK. 2
University of Edinburgh, John Hughes Bennett Laboratory, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK. 3
Cardiff School of Biosciences, Life Sciences Building, Museum Avenue, PO Box 911, Cardiff CF10 3US, UK. 4
Institute of Molecular Genetics, CNRS UMR-5535 and University of Montpellier II, Montpellier, France. 5
Present address: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. 6
These authors contributed equally to this work.
Correspondence should be addressed to Neil Brockdorff neil.brockdorff@csc.mrc.ac.uk Embryonic stem (ES) cells are important tools in the study of gene function and may also become important in cell therapy applications1. Establishment of stable XX ES cell lines from mouse blastocysts is relatively problematic owing to frequent loss of one of the two X chromosomes. Here we show that DNA methylation is globally reduced in XX ES cell lines and that this is attributable to the presence of two active X chromosomes. Hypomethylation affects both repetitive and unique sequences, the latter including differentially methylated regions that regulate expression of parentally imprinted genes. Methylation of differentially methylated regions can be restored coincident with elimination of an X chromosome in early-passage parthenogenetic ES cells, suggesting that selection against loss of methylation may provide the basis for X-chromosome instability. Finally, we show that hypomethylation is associated with reduced levels of the de novo DNA methyltransferases Dnmt3a and Dnmt3b and that ectopic expression of these factors restores global methylation levels.
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