Protein O-GlcNAcylation Promotes Trophoblast Differentiation at Implantation

Abstract

Embryo implantation begins with blastocyst trophectoderm (TE) attachment to the endometrial epithelium, followed by the breaching of this barrier by TE-derived trophoblast. Dynamic protein modification with O-linked β-N-acetylglucosamine (O-GlcNAcylation) is mediated by O-GlcNAc transferase and O-GlcNAcase (OGA), and couples cellular metabolism to stress adaptation. O-GlcNAcylation is essential for blastocyst formation, but whether there is a role for this system at implantation remains unexplored. Here, we used OGA inhibitor thiamet g (TMG) to induce raised levels of O-GlcNAcylation in mouse blastocysts and human trophoblast cells. In an in vitro embryo implantation model, TMG promoted mouse blastocyst breaching of the endometrial epithelium. TMG reduced expression of TE transcription factors Cdx2, Gata2 and Gata3, suggesting that O-GlcNAcylation stimulated TE differentiation to invasive trophoblast. TMG upregulated transcription factors OVOL1 and GCM1, and cell fusion gene ERVFRD1, in a cell line model of syncytiotrophoblast differentiation from human TE at implantation. Therefore O-GlcNAcylation is a conserved pathway capable of driving trophoblast differentiation. TE and trophoblast are sensitive to physical, chemical and nutritive stress, which can occur as a consequence of maternal pathophysiology or during assisted reproduction, and may lead to adverse neonatal outcomes and associated adult health risks. Further investigation of how O-GlcNAcylation regulates trophoblast populations arising at implantation is required to understand how peri-implantation stress affects reproductive outcomes.

Cell differentiation events in pre-implantation mouse and bovine embryos

“…These pathways would be involved in the O-glycosylation of YAP1, allowing nuclear translocation of YAP1, directly interfering in the first cell differentiation process and playing a decisive role in the specification of the trophectoderm (Chi et al, 2020). More specifically, pharmacological modulation of the O-GlcNAcylation process in pre-implantation stages proved to be important for future differentiation of trophoblast cells, interfering with the expression of transcription factors such as CDX2 and GATA3 (Ruane et al, 2020).…”

O-linked N-acetylglucosamine affects mitochondrial homeostasis by regulating Parkin-dependent mitophagy in hyperoxia-injured alveolar type II cells injury

“…Studies have shown that OSMI-1 can promote tumor cell apoptosis and has certain prospects for cancer treatment [ 39 , 40 ]. It has been shown to be negatively regulated in osteoclasts [ 41 ] and positively regulated during embryonic differentiation [ 42 ] and in corneal epithelial cells [ 43 ]. In this study, using in vitro experiments, we proved that the application of OSMI-1 to inhibit the function of OGT can improve the degree of damage to lung epithelial cells caused by hyperoxia, enhance cell metabolism and proliferation, decrease apoptosis, and promote cell cycle rates.…”

Protein O-GlcNAcylation as a nutrient sensor signaling placental dysfunction in hypertensive pregnancy

“…Protein O -GlcNAcylation has been implicated in embryonic development once the OGT enzyme was determined to be essential for embryonic stem cell viability and OGT depletion was related to embryonic lethality ( 29 , 30 ). Lately, O -GlcNAc was found to promote trophectoderm differentiation into invasive trophoblast, a pattern required during embryo implantation ( 31 ). These data could relate to our findings once SHR presented an increased number of pre-implantation losses along with reduced placental O -GlcNAc expression since 14 DOP.…”