Abstract
Sex differences are well known to be determinants of development, health and disease. Epigenetic mechanisms are also known to differ between men and women through X-inactivation in females. We hypothesized that epigenetic sex differences may also result from sex hormone functions, in particular from long-lasting androgen programming. We aimed at investigating whether inactivation of the androgen receptor, the key regulator of normal male sex development, is associated with differences of the patterns of DNA methylation marks in genital tissues. To this end, we performed large scale array-based analysis of gene methylation profiles on genomic DNA from labioscrotal skin fibroblasts of 8 males and 26 individuals with androgen insensitivity syndrome (AIS) due to inactivating androgen receptor gene mutations. By this approach we identified differential methylation of 167 CpG loci representing 162 unique human genes. These were significantly enriched for androgen target genes and low CpG content promoter genes. Additional 75 genes showed a significant increase of heterogeneity of methylation in AIS compared to a high homogeneity in normal male controls. Our data show that normal and aberrant androgen receptor function is associated with distinct patterns of DNA-methylation marks in genital tissues. These findings support the concept that transcription factor binding to the DNA has an impact on the shape of the DNA methylome. These data which derived from a rare human model suggest that androgen programming of methylation marks contributes to sexual dimorphism in the human which might have considerable impact on the manifestation of sex-associated phenotypes and diseases.
Highlights
A wealth of phenotypic dimorphisms differentiates males from females
While the most evident sexual dimorphism occurs in the genitalia, there are many extra-genital sites of the body characterized by sexual dimorphisms of anatomy and function including sex specific differentiation of the brain [1]
Fibroblasts were obtained from complete AIS (CAIS) individuals, partially virilized (ambiguous) genitalia (PAIS) individuals, one minimal AIS (MAIS) individual and 8 males with phenotypic normal male external genitalia
Summary
A wealth of phenotypic dimorphisms differentiates males from females. While the most evident sexual dimorphism occurs in the genitalia, there are many extra-genital sites of the body characterized by sexual dimorphisms of anatomy and function including sex specific differentiation of the brain [1]. Behavioral traits have a well-documented sex specificity already present in children [2,3]. Biological sex modifies risks for common disorders like asthma [8] and cardiovascular disease [9]. This indicates that sexual dimorphism is an important human phenotype modifier that can affect prevalence, course and severity of diseases [10]
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