Human Endometrial Transcriptome and Progesterone Receptor Cistrome Reveal Important Pathways and Epithelial Regulators

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.

Sex differences in neutrophil biology modulate response to type I interferons and immunometabolism

“…Estrogen regulates multiple STATs, important transcription factors for ISGs, by either enhancing their phosphorylation or DNA-binding activity (40)(41)(42)(43). The genomic-binding site of the progesterone receptor is enriched and overlaps with the binding sites of STAT1, STAT3, and STAT5, suggesting a role for progesterone in ISG activation (44). In contrast, while androgens can increase neutrophil recruitment to inflamed tissues (45-47) they reduce their bactericidal efficiency and ROS synthesis (48).…”

Expression and significance of estrogen receptor and progesterone receptor in endometrial tissue of patients with intrauterine adhesions

“…ER and PR can respectively recognize estrogen and progesterone with specific characteristics. When the receptor binds to the hormone to form a complex, it binds to the chromosome in an activated form, which causes gene activation and promotes, transcribes, and synthesizes new DNA, and then synthesizes new proteins, and promotes the growth and metabolism of endometrial cells through this type of proteins with biological functions (16,17). ER is highly expressed in the endometrium's proliferative stage and low in the ovulation stage; PR is highly expressed in the ovulation stage, while it shows a downward trend in endometrial gland increases in endometrial stromal cells (18).…”

The role of epigenetic mechanisms in the regulation of gene expression in the cyclical endometrium

“…The implantation is a complex progesterone-dependent event that involves several biological processes that occur in a coordinated fashion in the endometrium, such as cell adhesion, cell growth, differentiation, and signal transduction [ 23 , 35 ]. In a recent study, progesterone has been shown to regulate pathways related to the inflammatory response, xenobiotic metabolism, cell death, epithelial-mesenchymal transition and estrogen response during the window of implantation [ 36 ]. The implantation-associated gene clusters include several genes encoding growth factors, such as TGF α and PlGF .…”