Abstract
BackgroundSexual 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 zona pellucida binding protein 2 (ZPBP2) as a reporter.ResultsOur data show that the presence of the sex determining region Y (SRY) was associated with lower methylation levels, whereas higher X chromosome dosage in the absence of SRY led to an increase in DNA methylation levels at the ZPBP2 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 ATRX and RLIM genes, located in this region, on methylation levels. Neither ATRX nor RLIM mutations influenced ZPBP2 methylation in female carriers.ConclusionsWe 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.
Highlights
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
Sexual dimorphism in autosomal gene expression may result from different doses of transcription factors that are encoded by the sex chromosome-linked genes, especially those X-linked genes that escape X-inactivation
To test the impact of the sex-chromosome complement on autosomal DNA methylation levels in human cells, as a first step, we used human non-transformed fibroblast cell lines derived from donors with different combinations of sex-chromosome complement and sex that would permit separating the effects of sex chromosomes from those of sex phenotype (Additional file 3: Table S2 and Additional file 1: Figure S1)
Summary
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. Sexual dimorphism in autosomal gene expression may result from different doses of transcription factors that are encoded by the sex chromosome-linked genes, especially those X-linked genes that escape X-inactivation. It may arise as a consequence of sex-specific differences in methylation levels of regulatory elements. In females with Turner syndrome and monosomy X, global DNA methylation levels are lower than in 46,XX females, but higher than in 46,XY males [24, 25] This suggests that both sex chromosomes as well as gonadal hormones contribute to the establishment or maintenance of global DNA methylation patterns
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