Abstract
DNA methylation plays a key role in X-chromosome inactivation (XCI), a process that achieves dosage compensation for X-encoded gene products between mammalian female and male cells. However, differential sex chromosome dosage complicates genome-wide epigenomic assessments, and the X chromosome is frequently excluded from female-to-male comparative analyses. Using the X chromosome in the sexually dimorphic mouse liver as a model, we provide a general framework for comparing base-resolution DNA methylation patterns across samples that have different chromosome numbers and ask at a systematic level if predictions by historical analyses of X-linked DNA methylation hold true at a base-resolution chromosome-wide level. We demonstrate that sex-specific methylation patterns on the X chromosome largely reflect the effects of XCI. While our observations concur with longstanding observations of XCI at promoter-proximal CpG islands, we provide evidence that sex-specific DNA methylation differences are not limited to CpG island boundaries. Moreover, these data support a model in which maintenance of CpG islands in the inactive state does not require complete regional methylation. Further, we validate an intragenic non-CpG methylation signature in genes escaping XCI in mouse liver. Our analyses provide insight into underlying methylation patterns that should be considered when assessing sex differences in genome-wide methylation analyses.
Highlights
Mammalian females have two X chromosomes, while males have one
The Xi has long been associated with specific DNA methylation patterns, which play a key role in maintaining the inactive state[16,17,18,19,20], while the Xa displays allele-specific methylation concentrated at gene bodies[21]
We utilized a high-depth whole genome bisulfite sequencing dataset to draw insights on a longstanding topic of interest, the role of DNA methylation in X-chromosome inactivation (XCI), in a mouse model system widely used for toxicological assessments
Summary
Mammalian females have two X chromosomes, while males have one. Dosage compensation for X-linked genes between mammalian female (XX) and male (XY) individuals is achieved through transcriptional inactivation of one of the two X chromosomes in each female cell early in development[8]. While use of hybrid model systems can distinguish DNA methylation of Xi and Xa in the same cell population[28], for the vast majority of human (population) and animal studies, Xi and Xa are indistinguishable. For these studies, observed measurements represent an aggregate of two distinct populations, the Xi and Xa. Second, there is one male X chromosome for every two autosomes. We further investigated how these epigenetic modifications relate to dosage compensation of X-linked gene expression Through these efforts, we confirmed that previous locus-specific findings hold true at a chromosome-wide base-resolution scale and provide new insights about DNA methylation and silencing the Xi
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