X chromosome dosage and presence of <italic>SRY</italic> shape sex-specific differences in DNA methylation at an autosomal region in human cells.

Background: Sexual dimorphism in DNA methylation levels is a recurrent epigenetic feature in different human cell types and has been implicated in predisposition to disease, such as psychiatric and autoimmune disorders. To elucidate the genetic origins of sex-specific DNA methylation, we examined DNA methylation levels in fibroblast cell lines and blood cells from individuals with different combinations of sex chromosome complements and sex phenotypes focusing on a single autosomal region––the differentially methylated region (DMR) in the promoter of the <italic>zona pellucida</italic> binding protein 2 (<italic>ZPBP2</italic>) as a reporter. Results: Our data show that the presence of the sex determining region Y (<italic>SRY</italic>) was associated with lower methylation levels, whereas higher X chromosome dosage in the absence of <italic>SRY</italic> led to an increase in DNA methylation levels at the <italic>ZPBP2</italic> DMR. We mapped the X-linked modifier of DNA methylation to the long arm of chromosome X (Xq13-q21) and tested the impact of mutations in the <italic>ATRX</italic> and <italic>RLIM</italic> genes, located in this region, on methylation levels. Neither <italic>ATRX</italic> nor <italic>RLIM</italic> mutations influenced <italic>ZPBP2</italic> methylation in female carriers. Conclusions: We conclude that sex-specific methylation differences at the autosomal locus result from interaction between a Y-linked factor SRY and at least one X-linked factor that acts in a dose-dependent manner. [ABSTRACT FROM AUTHOR]