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Cited by 17Estrogen and related hormone effectsReproductive System and PregnancyGenomics and Chromatin Dynamics

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

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Whirledge, Shannon, Kisanga, Edwina P, Taylor, Robert N, Cidlowski, John A·2017·Endocrinology
DOI 10.1210/en.2017-00361PMC PMC5695839
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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.

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  • Dexamethasone treatment uniquely regulates expression of genes in mouse uterus and human uterine cell lines with functions related to signaling, embryonic development, and cellular growth and proliferation.

    “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]”

    From Stress and the HPA Axis: Balancing Homeostasis and Fertility. (2017) · cites this paper as [53]

    The Results section, “Glucocorticoids regulate LEFTY1 expression in primary and immortalized human uterine cell lines” (page unavailable), reports that dexamethasone induced LEFTY1 expression in human endometrial cells. Another Results section identifies additional dexamethasone-responsive genes, and the Discussion links some of them to signaling, embryonic development, or proliferation. The paper does not report dexamethasone-regulated gene expression in mouse uterus, so it does not support that part of the sentence. (LLM, conf=0.86)

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Cited by

Sorted by citations

Authors
Whirledge, S., Kisanga, E. P., Taylor, R. N., & Cidlowski, J. A.
Affiliations
  • Yale University (US)
  • Wake Forest University Health Sciences (US)
  • National Institute of Environmental Health Sciences (US)
Corresponding author
Cidlowski, John A
ORCID
Venue
Endocrinology
Publisher
The Endocrine Society
Published
2017-08-29
Volume
158
Issue
11
Pages
4076-4092
ISSN
  • 0013-7227 (ISSN-L)
  • 1945-7170
DOI
10.1210/en.2017-00361
PMC
PMC5695839
OpenAlex
W2751086386
Cited by
17
References
11
Citations by year
2025: 1 · 2024: 1 · 2023: 3 · 2021: 2 · 2020: 5 · 2019: 3 · 2017: 2
FWCI
1.82
Type
journal article
Language
en
Open access
Licence
Locations
  • Endocrinology (publishedVersion, public-domain)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of Environmental Health Sciences (R00ES022983)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
  • Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
FOXA1, FOXA2, glucocorticoid receptor, Lefty1, endometrial cells, estradiol, glucocorticoid signaling, decidualization, promoter recruitment, RNA polymerase II, gene expression regulation, endometrial receptivity, pregnancy
MeSH terms
Cells, Cultured, Dexamethasone, Endometrium, Estradiol, Female, Gene Expression Regulation, Glucocorticoids, Humans, Embryo Implantation, Promoter Regions, Genetic, Receptors, Glucocorticoid, Signal Transduction, Hepatocyte Nuclear Factor 3-alpha, Hepatocyte Nuclear Factor 3-beta, Left-Right Determination Factors

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