Pioneer Factors FOXA1 and FOXA2 Assist Selective Glucocorticoid Receptor Signaling in Human Endometrial Cells

Abstract

Successful pregnancy relies on dynamic control of cell signaling to achieve uterine receptivity and the necessary biological changes required for endometrial decidualization, embryo implantation, and fetal development. Glucocorticoids are master regulators of intracellular signaling and can directly regulate embryo implantation and endometrial remodeling during murine pregnancy. In immortalized human uterine cells, we have shown that glucocorticoids and estradiol (E2) coregulate thousands of genes. Recently, glucocorticoids and E2 were shown to coregulate the expression of Left-right determination factor 1 (LEFTY1), previously implicated in the regulation of decidualization. To elucidate the molecular mechanism by which glucocorticoids and E2 regulate the expression of LEFTY1, immortalized and primary human endometrial cells were evaluated for gene expression and receptor recruitment to regulatory regions of the LEFTY1 gene. Glucocorticoid administration induced expression of LEFTY1 messenger RNA and protein and recruitment of the glucocorticoid receptor (GR) and activated polymerase 2 to the promoter of LEFTY1. Glucocorticoid-mediated recruitment of GR was dependent on pioneer factors FOXA1 and FOXA2. E2 was found to antagonize glucocorticoid-mediated induction of LEFTY1 by reducing recruitment of GR, FOXA1, FOXA2, and activated polymerase 2 to the LEFTY1 promoter. Gene expression analysis identified several genes whose glucocorticoid-dependent induction required FOXA1 and FOXA2 in endometrial cells. These results suggest a molecular mechanism by which E2 antagonizes GR-dependent induction of specific genes by preventing the recruitment of the pioneer factors FOXA1 and FOXA2 in a physiologically relevant model.

Integrative analysis of the forkhead box A2 (FOXA2) cistrome for the human endometrium

“…Indeed, dynamic changes in FOXA2 and associated transcription factors in relation to gene expression programs occurs in the developing embryo (39) as well as in the liver (40). Furthermore, FOXA1 and FOXA2 act in concert with other nuclear receptors, including ESR1 and glucocorticoid receptor (41,42). Of note, FOXA2 is a tumor suppressor gene that is frequently mutated during the development of adenocarcinoma (22,23) and down-regulated in endometriosis (43).…”

Stress and the HPA Axis: Balancing Homeostasis and Fertility

“…Dexamethasone also blocks estrogen-induced uterine growth and proliferation in mice [ 51 ]. Dexamethasone treatment uniquely regulates the expression of genes in the mouse uterus and in human uterine cell lines with functions that are related to signaling, embryonic development, and cellular growth and proliferation [ 52 , 53 , 54 ] Epithelial cell proliferation prior to implantation is critical to establishing a receptive uterus. In the mouse uterus, dexamethasone blocks estrogen-mediated induction of insulin-like growth factor-I ( Igf-1 ), a key growth factor stimulating epithelial cell proliferation [ 55 , 56 , 57 ].…”

<p>Corticosteroids Prior to Embryo Transfer in Assisted Reproduction in Women with Crohn’s Disease and Ulcerative Colitis – A Nationwide Cohort Study</p>

“…4,8 It is known that the immune system is central to establishing endometrial receptivity and initiating a pregnancy, 4,22,23 and glucocorticoids are master regulators of intracellular signalling and can directly regulate embryo implantation and endometrial remodelling. 24,25 Most attention has been given to glucocorticoids as it has been proposed that these may improve the intrauterine environment by acting as immunomodulators to reduce the uterine natural killer cell count and normalise the cytokine expression profile in the endometrium and by suppression of endometrial inflammation. 8 Glucocorticoids have thus been advocated to improve the intrauterine environment, and perhaps improve embryo implantation in ART treatment.…”