Epigenetic differences identified between placentas of male and female fetuses

Methylation in the placentas of male and female fetuses has marked differences, according to a study by researchers at the National Institutes of Health, Bethesda, Maryland.

DNA methylation is an epigenetic mechanism that cells use to control gene expression. It occurs when a tag known as a methyl group is added to the DNA molecule without altering its underlying sequence. The addition of this tag allows the regulation of gene expression by turning genes 'on' or 'off'. Using multi-omics techniques, to determine the precise molecular changes which define cell types and their development, the researchers analysed the methylation patterns of 152 male and 149 female placental samples from a larger study. The placenta develops from cells that are part of the early embryo, and the researchers have identified differences between male and female placentas that may play a role in birthweight and adult diseases.

Publishing their findings in Nature Communications the authors wrote: 'This study offered several unique insights about the landscape of sex differences in the level and genetic regulation of methylation and gene expression in the human placenta… [The] findings suggest the potential role of placenta-mediated sex differences in developmental and later-life physiological traits and diseases.'

The researchers identified 6077 DNA sites with different methylation patterns between males and females, of which 2497 were previously unreported. Overall, 66.9 percent had higher methylation in DNA from male placentas, which were linked with greater neonatal size. The remaining 33.1 percent had higher methylation in DNA from female placentas and were linked to greater placental size.

Some increases in methylation were sex specific, such as DNA sites near the CCDC6 gene in males and the NIRF1 gene in females. Reduced expression of these genes has been previously linked to preterm deliveries and preeclampsia, respectively.

The authors found that higher methylation near the FNDC5 gene was associated with lower expression of the gene in male placentas but not in female placentas. FNDC5 is involved in the production of irisin, which protects the placenta from damage by reactive oxygen molecules and insulin resistance. Lower irisin levels have been associated with preeclampsia and lower placental weight.

Additionally, the researchers identified variations in the ATP5MG and FAM83A genes expressed in the female placenta that have been associated with asthma, hay fever, eczema and breast cancer.

The authors noted that their study was unable to distinguish sex differences that emerged in early gestation from those that emerged in later gestation. For example, a previous methylation study on first trimester placentas found that ZNF300 was highly methylated in male but not female placentas (see BioNews 1262), which was similarly observed in the present study.

Dysfunction of the placenta underlies many pregnancy complications and is thought to determine male and female health differences that occur later in life. The differences in DNA methylation uncovered in this study could support future research on the higher risk for pregnancy complications involving male fetuses, such as stillbirth and prematurity.