Exploratory analysis of differences at the transcriptional interface between the maternal and fetal compartments of the sheep placenta and potential influence of fetal sex

Abstract

An understanding of the inner workings of the placenta is imperative to elucidate how the maternal and fetal compartments coordinate to mediate fetal development. The two compartments can be separated and studied before term in sheep, a feat not possible in humans, thus providing a valuable translational model. This study investigated differential expression of gene signaling networks in the maternal and fetal compartments of the placenta and explored the potential influence of fetal sex. On approximately gestational day 120 (term: 147 days), ewes were euthanized and fetuses removed and sexed. Placentomes [n = 5 male, n = 3 female] were collected, and caruncles (maternal) and cotyledons (fetal) were separated and sequenced to assess RNA expression. Analysis revealed 2627 differentially expressed genes (FDR<0.01, abslog2FC ≥ 2) contributing to key transcriptional differences between maternal and fetal compartments, which suggested that the maternal compartment drives extracellular signaling at the interface whereas the fetal compartment controls internal mechanisms crucial for fetal-placental development. X-chromosome inactivation equalized expression of a vast majority of X-linked genes in the fetal compartment. Additionally, the female placenta had more fine-tuned regulation of key pathways for fetal-placental development, such as DNA replication, mRNA surveillance, and RNA transport, compared to males, which had enrichment of metabolic pathways including TCA cycle and galactose metabolism. These findings, in addition to supporting differences in expression in the maternal and fetal placental compartments and the possible influence of fetal sex, offer a transcriptional platform to compare placental perturbations that occur at the maternal-fetal interface that contribute to adverse pregnancy outcomes.

Keywords: Placenta; RNA sequencing; sex differences.