The role of epithelial Progesterone Receptor Isoforms in embryo implantation [ChIPseq-PGR-H3K27AC]

RNA-seq analysis of uterine luminal epithelium at D4.5 indicates that epithelial PGRA and PGRB shares conseved pathways. Constitutive epithelial PGRA and PGRB disrupts the embryo implantation both through the suppressed FOXO1 signaling by excluding FOXO1 from the nuclear at the uterine epithelium. There are three layers of regulation. Firstly, PGRA and PGRB diminishes Lif transcription in uterine glands by blocking ESR1 binding at the Lif promoter at D3.5 which is critical for the FOXO1 nuclear expression at D4.5 through LIF/pSTAT3/FOXO1. Secondly, PGRA and PGRB directly suppres Foxo1 transcription at the uterine epithelium probably through direct binding at Foxo1 promoter. Thirdly, PGRA and PGRB promotes the Sgk1 transcription, the kinases that phosphorylate FOXO1 to translocate it into cytoplasma for degradation. Overall design: PgrcrePgrALsL/+ and PgrcrePgrBLsL/+ mice were ovariectomized for 2 weeks. And the whole uterus were collected for PGR ChIP-Seq after 1h progesterone treatment. Wildtype mouse were mated with stud males. The day the vaginal plug detected was defined as pregnant day 0.5. The uterus were collected at pregnant day 3.5 for H3K27AC ChIP-Seq.