Peg3 Deficiency Results in Sexually Dimorphic Losses and Gains in the Normal Repertoire of Placental Hormones

Abstract

Hormones from the fetally derived placenta signal to the mother throughout pregnancy to ensure optimal fetal growth and prepare the mother for her new role in nurturing her offspring. Through evolution, placental hormones have under gone remarkable diversification and species-specific expansions thought to be due to constant rebalancing of resource allocation between mother and offspring. Genomic imprinting, an epigenetic process in which parental germlines silence genes in the offspring, is thought to be the physical embodiment of a second conflicting interest, between the male and female mammal. Several genes silenced by paternal imprints normally function to limit the placental endocrine lineages of the mouse placenta. We hypothesized that paternal imprinting has adapted to overcome the rapid evolution of placental hormone gene families by directly regulating the lineages that express these hormones rather than individual hormones. This predicts the existence of genes maternally silenced in the offspring counteracting the influence of the paternal imprint. Here we report on the consequences of loss of function of Paternally expressed gene 3 (Peg3), on placental endocrine lineages. Mutant male placenta displayed a marked loss of the spongiotrophoblast, a key endocrine lineage of the placenta, and the glycogen cell lineage alongside reduced stores of placental glycogen and changes in expression of the normal repertoire of placental hormones. Peg3 is known to transcriptionally repress placental hormone genes. Peg3 consequently both positively and negatively regulates placental hormones through two independent and opposing mechanisms. Female placenta showed moderate response to loss of Peg3 with minor alterations to the junctional zone lineages and few changes in gene expression. These data highlight the important fact that female placenta compensate for the loss of Peg3 better than male placenta. This work lends further support to our novel hypothesis that the parental genomes are competing over the endocrine function of the mouse placenta and further suggests that a conflict between males and females begins in utero.

Obesity and regulation of human placental lactogen production in pregnancy

“…If PEG3 is restricted to villus cytotrophoblasts in the human placenta, this raises a possible role for PEG3 repression of hPL gene expression. This would be consistent with reports of repression of mPL2 gene expression by PEG3 in the spongiotrophoblast cells of the mouse placenta 82,83 . PEG3‐related repression of the hPL genes in the villous cytotrophoblast would in turn open the possibility for de‐repression in the syncytiotrophoblast.…”

Fetal sex and maternal postpartum depressive symptoms: findings from two prospective pregnancy cohorts

“…For example, PEG3 is an imprinted gene that plays important roles in controlling fetal growth and nurturing behaviors. Murine models have demonstrated loss of Peg3 expression has sexually dimorphic consequences for placental function [ 63 ], including the expression of hormones, and influences maternal behavior [ 64 ].…”

Assisted reproductive technologies induce temporally specific placental defects and the preeclampsia risk marker sFLT1 in mouse

“…To ascertain whether an association exists between these DNA methylation changes and the morphological phenotypes over the span of placenta development, we measured DNA methylation of the paternally methylated ICR H19/Igf2 and three maternally methylated ICRs -Kcnq1ot1, Peg3 and Snrpnby bisulfite pyrosequencing. These loci were chosen due to their known role in human imprinting disorders and known function in placental and fetal growth (Rhon-Calderon et al, 2019;Tunster et al, 2013Tunster et al, , 2018. Because ICRs exhibit methylation on one parental allele, assay of bulk DNA results in ∼50% methylation.…”