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UBC Theses and Dissertations

Patterns of DNA methylation on the human X chromosome and use in analyzing X-chromosome inactivation Cotton, Allison Marie


The process of X-chromosome inactivation achieves dosage compensation between mammalian males and females. In females one X chromosome is transcriptionally silenced through a variety of epigenetic modifications including DNA methylation. Most X-linked genes are subject to X-chromosome inactivation and only expressed from the active X chromosome. On the inactive X chromosome, the CpG island promoters of genes subject to X-chromosome inactivation are methylated in their promoter regions, while genes which escape from Xchromosome inactivation have unmethylated CpG island promoters on both the active and inactive X chromosomes. The first objective of this thesis was to determine if the DNA methylation of CpG island promoters could be used to accurately predict X chromosome inactivation status. The second objective was to use DNA methylation to predict X-chromosome inactivation status in a variety of tissues. A comparison of blood, muscle, kidney and neural tissues revealed tissue-specific X-chromosome inactivation, in which 12% of genes escaped from X-chromosome inactivation in some, but not all, tissues. X-linked DNA methylation analysis of placental tissues predicted four times higher escape from X-chromosome inactivation than in any other tissue. Despite the hypomethylation of repetitive elements on both the X chromosome and the autosomes, no changes were detected in the frequency or intensity of placental Cot-1 holes. The third objective of this thesis was to use DNA methylation to investigate X-chromosome inactivation in female samples with chromosomally abnormal karyotypes. The spread of Xchromosome inactivation into the autosomal portion of six unbalanced X;autosome translocations revealed similarities between X;autosome translocations involving the same autosome and therefore suggested a role for DNA sequence in influencing X-chromosome inactivation status of genes. Autosomal genes that escaped from inactivation were found to have significantly lower L1 and LTR but higher Alu content than genes which were subject to inactivation. Lastly, DNA methylation was used to predict the number of inactive X chromosomes in triploid placental samples. Triploid samples provide an excellent system in which to study the counting step of X-chromosome inactivation and DNA methylation analysis provides a means to determine the number of inactive X chromosomes using only a DNA sample.

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