DNA methylation profiles of human active and inactive X chromosomes

  1. Stylianos E. Antonarakis1
  1. 1Department of Genetic Medicine and Development, University of Geneva, 1211 Geneva 4, Switzerland;
  2. 2Swiss Institute of Bioinformatics, University of Lausanne, 1015 Lausanne, Switzerland;
  3. 3Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York 10029, USA
    • 4 Present address: Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA.

    Abstract

    X-chromosome inactivation (XCI) is a dosage compensation mechanism that silences the majority of genes on one X chromosome in each female cell. To characterize epigenetic changes that accompany this process, we measured DNA methylation levels in 45,X patients carrying a single active X chromosome (Xa), and in normal females, who carry one Xa and one inactive X (Xi). Methylated DNA was immunoprecipitated and hybridized to high-density oligonucleotide arrays covering the X chromosome, generating epigenetic profiles of active and inactive X chromosomes. We observed that XCI is accompanied by changes in DNA methylation specifically at CpG islands (CGIs). While the majority of CGIs show increased methylation levels on the Xi, XCI actually results in significant reductions in methylation at 7% of CGIs. Both intra- and inter-genic CGIs undergo epigenetic modification, with the biggest increase in methylation occurring at the promoters of genes silenced by XCI. In contrast, genes escaping XCI generally have low levels of promoter methylation, while genes that show inter-individual variation in silencing show intermediate increases in methylation. Thus, promoter methylation and susceptibility to XCI are correlated. We also observed a global correlation between CGI methylation and the evolutionary age of X-chromosome strata, and that genes escaping XCI show increased methylation within gene bodies. We used our epigenetic map to predict 26 novel genes escaping XCI, and searched for parent-of-origin-specific methylation differences, but found no evidence to support imprinting on the human X chromosome. Our study provides a detailed analysis of the epigenetic profile of active and inactive X chromosomes.

    Footnotes

    • Received July 9, 2010.
    • Accepted July 7, 2011.
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