Sirohi Vijay K, Medrano Theresa I, Kannan Athilakshmi, Bagchi Indrani C, Cooke Paul S
Department of Physiological Sciences, University of Florida, Gainesville, FL, USA.
Department of Comparative Biosciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
iScience. 2023 Jun 8;26(7):107028. doi: 10.1016/j.isci.2023.107028. eCollection 2023 Jul 21.
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 conditional knockout (cKO) mouse to determine EZH2's role in pregnancy progression. Despite normal fertilization and implantation, embryo resorption occurred mid-gestation in cKO mice, accompanied by compromised decidualization and placentation. Western blot analysis revealed -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 cKO 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.
母体子宫重塑有助于胚胎着床、基质细胞蜕膜化和胎盘形成，这些过程受到干扰可能会导致妊娠丢失。zeste同源物2增强子（EZH2）是一种组蛋白甲基转移酶，可通过表观遗传方式抑制基因转录；子宫EZH2缺失会影响子宫内膜生理功能并导致不孕。我们利用子宫条件性敲除（cKO）小鼠来确定EZH2在妊娠进程中的作用。尽管受精和着床正常，但cKO小鼠在妊娠中期出现胚胎吸收，同时伴有蜕膜化和胎盘形成受损。蛋白质免疫印迹分析显示，EZH2缺陷的基质细胞中组蛋白甲基化标记H3K27me3的含量减少，导致衰老标记物p21和p16上调，这表明基质细胞衰老加剧可能会损害蜕膜化。妊娠第12天（GD12）的cKO母鼠的胎盘显示出结构缺陷，包括海绵滋养层细胞定位错误和血管化减少。总之，子宫Ezh2缺失会损害蜕膜化，增加蜕膜衰老，并改变滋养层细胞分化，导致妊娠丢失。
