In utero, females limit their growth, thereby maintaining a greater placental reserve capacity. Males on the other hand, extract maximal nutrients from their placenta which likely underpins the consistent observation that males are born heavier than females. The mechanisms that give rise to these sex differences are unknown. Previous work in our laboratory has revealed sex biased gene expression in the term placenta from uncomplicated pregnancies in an integrative meta-analysis. It was found that > 140 genes were differentially expressed between male and female placentas, > 60 % of these genes were autosomal. A possible mechanism for these sex differences is DNA methylation, however it is unknown if autosomal DNA methylation patterns differ between male and female placentas. We hypothesised that the sex differences in gene expression evident in the term placenta are the result of altered DNA methylation patterns.
To test our hypothesis, we undertook a bioinformatic approach by combining six publically available DNA methylation microarray datasets, featuring term placental tissue from 45 uncomplicated pregnancies (42 % male, 58 % female), thereby maximising statistical power. All P-values were corrected for false discovery by calculating the family wide error rate (FWER). We identified > 160 differentially methylated regions (DMRs) when comparing male and female placentas (p < 0.05, FWER < 0.01). The DMRs were all situated on the sex chromosomes with > 80 % from the X chromosome. We then mapped these DMRs to the genome, to determine if they related to placental gene expression. It was found in many cases that DNA methylation was correlated with gene expression. For example XIST was found to be hypermethylated in males compared to females, but is expressed more highly in females. These results indicate that DNA methylation may be an underlying mechanism for some of the sex differences in placental gene expression.