Dosage compensation and DNA methylation landscape of the X chromosome in mouse liver

Sci Rep. 2018 Jul 4;8(1):10138. doi: 10.1038/s41598-018-28356-3.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CpG Islands
  • DNA Methylation*
  • Female
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • X Chromosome / genetics
  • X Chromosome Inactivation*