摘要：SummaryThe loss of uterine epithelial progesterone receptor (PGR) is crucial for successful embryo implantation in both humans and mice. The two major isoforms PGRA and PGRB have divergent functions under both physiological and pathological conditions. The present study compares phenotypes and gene signatures of PGRA and PGRB in uterine epithelium using uterine epithelial-specific constitutively expressed PGRA or PGRB mouse models. The cistrome and transcriptome analysis reveals substantial overlap between epithelial PGRA and PGRB, and both disrupt embryo implantation through FOXO1 pathways. Constitutive epithelial PGRA and PGRB expression impairs ESR1 occupancy at the promoter ofLifleading to reducedLiftranscription and further exaggerates SGK1 expression leading to enhanced PI3K-SGK1 activities, and both contribute to the decline of nuclear FOXO1 expression. Our study demonstrates that PGRA and PGRB in the uterine epithelium act on a similar set of target genes and commonly regulate the LIF-SGK1-FOXO1 signaling pathway for embryo implantation.Graphical abstractDisplay OmittedHighlights•PGRA and PGRB share conserved cistrome and transcriptome•Epithelial PGRA and PGRB overexpression disrupt embryo implantation•Epithelial PGR suppressesLiftranscription by blocking ESR1-binding Lif enhancer region•Epithelial PGR reduces nuclear FOXO1 by stimulating Sgk1 expressionDevelopmental biology; Embryology; Transcriptomics
