Ru-Pin Alicia Chi1, Tianyuan Wang2, Nyssa Adams3, San-Pin Wu1, Steven L Young4, Thomas E Spencer5,6, Francesco DeMayo1. 1. Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, North Carolina. 2. Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, North Carolina. 3. Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas. 4. Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. 5. Division of Animal Sciences, University of Missouri, Columbia, Missouri. 6. Department of Obstetrics, Gynecology and Women's Health, University of Missouri, Columbia, Missouri.
Abstract
CONTEXT: Poor uterine receptivity is one major factor leading to pregnancy loss and infertility. Understanding the molecular events governing successful implantation is hence critical in combating infertility. OBJECTIVE: To define Progesterone Receptor (PGR)-regulated molecular mechanisms and epithelial roles in receptivity. DESIGN: RNA-sequencing and PGR-ChIP-seq were conducted in parallel to identify PGR-regulated pathways during the Window of implantation (WOI) in endometrium of fertile women. SETTING: Endometrial biopsies from the proliferative and mid-secretory phases were analyzed. PATIENTS OR OTHER PARTICIPANTS: Participants were fertile, reproductive aged (18-37 years) women with normal cycle length, and without any history of dysmenorrhea, infertility, or irregular cycles. In total, 42 endometrial biopsies obtained from 42 women were analyzed in this study. INTERVENTIONS: There were no interventions during this study. MAIN OUTCOME MEASURES: Here we measured the alterations in gene expression and PGR occupancy in the genome during the WOI, based on the hypothesis that PGR binds uterine chromatin cycle dependently to regulate genes involved in uterine cell differentiation and function. RESULTS: 653 genes were identified with regulated PGR binding and differential expression during the WOI. These were involved in regulating inflammatory response, xenobiotic metabolism, epithelial mesenchymal transition, cell death, interleukin/Signal Transducer And Activator Of Transcription (STAT) signaling, estrogen response, and Mammalian target of rapamycin complex 1 (MTORC1) response. Transcriptome of the epithelium identified 3052 differentially expressed genes, of which 658 were uniquely regulated. Transcription factors Interferon Regulatory Factor 8 (IRF8) and Myocyte Enhancer Factor 2C (MEF2C) were found to be regulated in the epithelium during the WOI at the protein level, suggesting potentially important functions that are previously unrecognized. CONCLUSION: PGR binds the genomic regions of genes regulating critical processes in uterine receptivity and function. Published by Oxford University Press on behalf of the Endocrine Society 2019.
CONTEXT: Poor uterine receptivity is one major factor leading to pregnancy loss and infertility. Understanding the molecular events governing successful implantation is hence critical in combating infertility. OBJECTIVE: To define Progesterone Receptor (PGR)-regulated molecular mechanisms and epithelial roles in receptivity. DESIGN: RNA-sequencing and PGR-ChIP-seq were conducted in parallel to identify PGR-regulated pathways during the Window of implantation (WOI) in endometrium of fertile women. SETTING: Endometrial biopsies from the proliferative and mid-secretory phases were analyzed. PATIENTS OR OTHER PARTICIPANTS: Participants were fertile, reproductive aged (18-37 years) women with normal cycle length, and without any history of dysmenorrhea, infertility, or irregular cycles. In total, 42 endometrial biopsies obtained from 42 women were analyzed in this study. INTERVENTIONS: There were no interventions during this study. MAIN OUTCOME MEASURES: Here we measured the alterations in gene expression and PGR occupancy in the genome during the WOI, based on the hypothesis that PGR binds uterine chromatin cycle dependently to regulate genes involved in uterine cell differentiation and function. RESULTS: 653 genes were identified with regulated PGR binding and differential expression during the WOI. These were involved in regulating inflammatory response, xenobiotic metabolism, epithelial mesenchymal transition, cell death, interleukin/Signal Transducer And Activator Of Transcription (STAT) signaling, estrogen response, and Mammalian target of rapamycin complex 1 (MTORC1) response. Transcriptome of the epithelium identified 3052 differentially expressed genes, of which 658 were uniquely regulated. Transcription factors Interferon Regulatory Factor 8 (IRF8) and Myocyte Enhancer Factor 2C (MEF2C) were found to be regulated in the epithelium during the WOI at the protein level, suggesting potentially important functions that are previously unrecognized. CONCLUSION:PGR binds the genomic regions of genes regulating critical processes in uterine receptivity and function. Published by Oxford University Press on behalf of the Endocrine Society 2019.
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