UC San Diego

Implantation is the critical initial step for successful pregnancy at which the blastocyst comes into contact with the uterine endometrium, invades into the stroma, and establishes the placenta. Emerging evidence reveals the significant roles of lysophosphatidic acid (LPA) signaling, cyclooxygenase-2 (COX-2)-derived prostaglandins, and various microRNAs during the window of implantation. However, little has been known about how these important regulators interact with each other to coordinate the complex process of uterine receptivity, mainly due to the lack of in vitro systems to study the signaling pathways governing embryo implantation. Here, we report for the first time, a mouse endometrial epithelial cell line that allows for dissection of the molecular mechanisms of LPA receptor 3 (LPA₃)-mediated COX-2 expression. Critical regulation of this LPA₃-COX-2 pathway is accomplished through modulation of microRNA 143 and CUG triplet repeat- binding protein 2 (CUGBP2), providing additional layers of gene expression control resulting in a receptive uterine environment for implantation. Recently, fluctuations of histone acetylation have been observed in the human endometrium during the menstrual cycle, suggesting that epigenetic regulation may also play a role in preparing the uterus for successful pregnancy. This led us to speculate that modifications of histones, such as histone acetylation, might be involved in the regulation of LPA₃ gene (Lpar3) expression during implantation. Histone deacetylase (HDAC) inhibitors block deacetylation of histones, causing accumulation of acetyl-histones in the chromatin and thereby inducing gene expression. While increasing numbers of structurally diverse HDAC inhibitors have been identified, clinical and experimental usage has been focused on their implications for disease therapy. Here, we provide evidence for a novel application of HDAC inhibitors in enhancing uterine receptivity via epigenetic regulation of Lpar3 expression during the window of implantation. Understanding receptor-mediated LPA signaling mechanisms central to embryo implantation will provide a foundation for future endeavors toward improved fertility and successful contraception