The role of epithelial progesterone receptor isoforms in embryo implantation
Rong Li,
Xiaoqiu Wang,
Zhenyao Huang,
Jayani Balaji,
Tae Hoon Kim,
Tianyuan Wang,
Lecong Zhou,
Ashley Deleon,
Molly E. Cook,
Margeaux W. Marbrey,
San-Pin Wu,
Jae Wook Jeong,
Ripla Arora,
Francesco J. DeMayo
Affiliations
Rong Li
Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC 27709, USA
Xiaoqiu Wang
Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC 27709, USA
Zhenyao Huang
School of Public Health, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China
Jayani Balaji
Department of Obstetrics, Gynecology and Reproductive Biology, Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing 48823, MI, USA; Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University, East Lansing 48823, MI, USA
Tae Hoon Kim
Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University, East Lansing 48823, MI, USA
Tianyuan Wang
Integrative Bioinformatics, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC 27709, USA
Lecong Zhou
Integrative Bioinformatics, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC 27709, USA
Ashley Deleon
Laser Capture Microdissection Core Laboratory, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC 27709, USA; Kelly Government Solutions, Rockville, MD, 20852, USA
Molly E. Cook
Epigenomics and DNA Sequencing Core, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC 27709, USA
Margeaux W. Marbrey
Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC 27709, USA
San-Pin Wu
Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC 27709, USA
Jae Wook Jeong
Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University, East Lansing 48823, MI, USA
Ripla Arora
Department of Obstetrics, Gynecology and Reproductive Biology, Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing 48823, MI, USA; Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University, East Lansing 48823, MI, USA
Francesco J. DeMayo
Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC 27709, USA; Corresponding author
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.
