Author:
Sharp Andrew J.,Stathaki Elisavet,Migliavacca Eugenia,Brahmachary Manisha,Montgomery Stephen B.,Dupre Yann,Antonarakis Stylianos E.
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.
Publisher
Cold Spring Harbor Laboratory
Subject
Genetics (clinical),Genetics
Reference42 articles.
1. Bailey TL , Elkan C . 1994. Fitting a mixture model by expectation maximization to discover motifs in biopolymers. Proceedings of the Second International Conference on Intelligent Systems for Molecular Biology, pp. 28–36. AAAI Press, Menlo Park, CA.
2. A Morphological Distinction between Neurones of the Male and Female, and the Behaviour of the Nucleolar Satellite during Accelerated Nucleoprotein Synthesis
3. Controlling the false discovery rate: a practical and powerful approach to multiple testing;J R Stat Soc Ser B Methodol,1995
4. DNA methylation of the X chromosomes of the human female: an in situ semi-quantitative analysis
5. CpG Island Mapping by Epigenome Prediction
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