Psg22 expression in mouse trophoblast giant cells is associated with gene inversion and co-expression of antisense long non-coding RNAs

Abstract

Pregnancy-specific glycoproteins (PSGs) are secreted carcinoembryonic antigen (CEA)-related cell adhesion molecules-related members of the immunoglobulin superfamily and are encoded by multigene families in species with haemochorial placentation. PSGs may be the most abundant trophoblast-derived proteins in human maternal blood in late pregnancy and there is evidence that dysregulation of PSG expression is associated with gestational pathology. PSGs are produced by syncytiotrophoblast in the human placenta and by trophoblast giant cells (TGCs) and spongiotrophoblast in rodents, and are implicated in immune regulation, angiogenesis and regulation of platelet function. PSGs are encoded by 17 genes in the mouse and ten genes in the human. While functions appear to be conserved, the typical protein domain organisation differs between species. We analysed the evolution of the mouse Psg genomic locus structure and report inversion of the Psg22 gene within the locus. Psg22 is the most abundant Psg transcript detected in the first half of mouse pregnancy and we identified antisense long non-coding RNA (lncRNA) transcripts adjacent to Psg22 associated with an active local chromatin conformation. This suggests that an epigenetic regulatory mechanism may underpin high Psg22 expression relative to the other Psg gene family members in TGCs.

Pregnancy-specific glycoproteins: evolution, expression, functions and disease associations

“…The major site of PSG gene expression is the trophoblast of the fetal part of the placenta. Strong expression is seen in all examined trophoblastic lineages including rodent trophoblast giant cells and spongiotrophoblast, and human syncytiotrophoblast (Rebstock et al 1993, Zhou et al 1997a, Wynne et al 2006, Blois et al 2012, Williams et al 2015. More recently, human PSG expression has been reported in the human EVT, the trophoblast lineage that invades the endometrium (Rattila et al 2019).…”

“…The human, mouse and horse PSG families have 11, 17 and 7 genes, respectively, and orthologous relationships are not evident between these species. However, some orthologous gene pairs can be identified between mouse and rat (Williams et al 2015) and between human and apes (Zimmermann & Kammerer 2021). In addition to species-level divergence, the PSG locus may be the most prone to copy number variation in the human genome (Chang et al 2013, Dumont & Eichler 2013.…”

Targeted disruption ofPparγ1promotes trophoblast endoreplication in the murine placenta

“…7D). Psg22 was reported to be expressed predominantly in the early stage of TGCs during pregnancy (Williams et al, 2015), which might represent an immature state in sinusoidal TGCs. In addition, the expression of prolactin-related genes (Prls) was dysregulated (Wynne et al, 2006)…”

Psg22 null mouse embryos develop normally under normoxic and hypoxic conditions of pregnancy     

“…We did not analyse maternal gestational physiology in Psg22 mutant strains. However, unlike human PSGs that are present at high levels in maternal blood, mouse PSGs appear to be rapidly degraded in the maternal bloodstream and do not exhibit significant steady-state levels [13] [18] [19], suggesting that a significant effect on maternal physiology may be unlikely. PSG gene families may have evolved due to maternal-fetal conflict, and a prediction of this theory is that high expression levels of conflictor genes may result from mutually antagonistic interactions, but with a small net effect on phenotype [20] [21].…”

“…Therefore, mouse Psg gene mutants may provide models of human gestational disease. PSG mRNA in the first half of mouse pregnancy is almost exclusively derived from Psg22 in trophoblast giant cells (TGC), which may be due toinversion of the Psg22 gene and duplication of a long noncoding RNA (lncRNA) within the Psg locus [12] [13]. This expression pattern facilitates ablation of mouse Psg expression at this developmental stage without having to delete multiple Psg genes.…”