The role of epithelial progesterone receptor isoforms in embryo implantation

The 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 signatu...

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Published iniScience Vol. 24; no. 12; p. 103487
Main Authors Li, Rong, Wang, Xiaoqiu, Huang, Zhenyao, Balaji, Jayani, Kim, Tae Hoon, Wang, Tianyuan, Zhou, Lecong, Deleon, Ashley, Cook, Molly E., Marbrey, Margeaux W., Wu, San-Pin, Jeong, Jae Wook, Arora, Ripla, DeMayo, Francesco J.
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 17.12.2021
Elsevier
Subjects
Developmental biology
Embryology
Transcriptomics
Developmental biology
Transcriptomics
Embryology
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Summary:The 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 of Lif leading to reduced Lif transcription 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. [Display omitted] •PGRA and PGRB share conserved cistrome and transcriptome•Epithelial PGRA and PGRB overexpression disrupt embryo implantation•Epithelial PGR suppresses Lif transcription by blocking ESR1-binding Lif enhancer region•Epithelial PGR reduces nuclear FOXO1 by stimulating Sgk1 expression Developmental biology; Embryology; Transcriptomics
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ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2021.103487