Pregnant women and their fetuses may be impacted disproportionally by emerging infections 1 as exemplified by the 2009 H1N1 influenza pandemic 2 and the severe fetal complications of Zika virus. 3,4 The novel coronavirus infection, severe acute respiratory coronavirus 2 (SARS-CoV-2), was first reported in Wuhan, China, on December 31, 2019, and was declared a pandemic by the WHO on March 11, 2020. 5 Since then, the number of worldwide reported cases of COVID-19 has increased to 6.11 million and 370,000 deaths as of May 31, 2020. 6 To combat the rapidly spreading virus, nations have implemented strategies to suppress and mitigate the community-acquired infections such as social distancing, availability of rapid testing, contact tracing, and vaccine development. 7,8 Coronaviruses are single-stranded RNA, enveloped, non-segmented viruses which cause complications ranging from common cold to pneumonia and death. 9 Common symptoms of SARS-CoV-2 infection include fever, cough, myalgia, headache, and diarrhea. 10 Highly infective, the virus is transmitted to 2-3 people for every infected person, with a reproduction number (R0) of 2.2. 11 While

These findings suggest that glucocorticoids regulate extravillous trophoblast functions by altering the gene expression profile, which may contribute to the pathogenesis of reproductive disorders such as preeclampsia and IUGR.

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.

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