Grant: Travel Awards - Institute Community Support

During human menstrual cycle a dramatic transcriptional reprogramming of endometrial stromal cells occurs, leading to a receptive state of the endometrium in a process known as decidualization.Multiple transcriptional regulators have been identified that are essential for decidualization of stromal cells. Lrh-1 is an orphan nuclear receptor and a transcriptional regulator known to be involved in many reproductive events. Our studies showed that Lrh-1 is expressed in the mouse uterus and is essential for proper decidualization of the endometrial stroma. We have further demonstrated its occurrence in human endometrium during both the secretory and proliferative phases of the menstrual cycle. Our goal is to define the Lrh-1 transcriptional network regulating reprogramming of stromal cells into decidual cells by characterizing the gene expression pattern during decidual fibroblast differentiation. To address this hypothesis, we employed an in vitro model using a human endometrial stromal cell line (hESC). Our experiments demonstrated that the hESC cell line can undergo decidualization in vitro when treated with the progestin medroxyprogesterone acetate (MPA) and cAMP. The expression of Lrh-1 increases multiple fold during decidualization in vitro, parallel with increased expression of the markers for decidualization, prolactin (PRL)and insulin like growth factor binding protein-1 (IGFBP1) gene activation. To assess the effect of an Lrh-1 overexpression, we created a model by transfecting the cells with a construct constitutively expressing Lrh-1, resulting in 5 fold increases in abundance of transcripts for the decidualization marker genes PRL and IGFBP and a precrocious development of the decidual reaction. Moreover, ChIP-seq analysis demonstrated that PRL has a distal Lrh-1 binding site at -170kb from the PRL transcription start site.These results indicate that Lrh-1 regulates distinct sets of target genes during decidualization of the human stroma.