Uterine-specific Ezh2 deletion enhances stromal cell senescence and impairs placentation, resulting in pregnancy loss

Maternal uterine remodeling facilitates embryo implantation, stromal cell decidualization and placentation, and perturbation of these processes may cause pregnancy loss. Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that epigenetically represses gene transcription; loss of uterine EZH2 affects endometrial physiology and induces infertility. We utilized a uterine Ezh2 conditional knockout (cKO) mouse to determine EZH2’s role in pregnancy progression. Despite normal fertilization and implantation, embryo resorption occurred mid-gestation in Ezh2cKO mice, accompanied by compromised decidualization and placentation. Western blot analysis revealed Ezh2-deficient stromal cells have reduced amounts of the histone methylation mark H3K27me3, causing upregulation of senescence markers p21 and p16 and indicating that enhanced stromal cell senescence likely impairs decidualization. Placentas from Ezh2cKO dams on gestation day (GD) 12 show architectural defects, including mislocalization of spongiotrophoblasts and reduced vascularization. In summary, uterine Ezh2 loss impairs decidualization, increases decidual senescence, and alters trophoblast differentiation, leading to pregnancy loss.