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A common allele increases endometrial Wnt4 expression, with antagonistic implications for pregnancy, reproductive cancers, and endometriosis

Author

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  • Mihaela Pavličev

    (Cincinnati Children’s Hospital Medical Center
    University of Vienna
    Complexity Science Hub)

  • Caitlin E. McDonough-Goldstein

    (University of Vienna)

  • Andreja Moset Zupan

    (Cincinnati Children’s Hospital Medical Center)

  • Lisa Muglia

    (Cincinnati Children’s Hospital Medical Center)

  • Yueh-Chiang Hu

    (Cincinnati Children’s Hospital Medical Center
    University of Cincinnati College of Medicine)

  • Fansheng Kong

    (Cincinnati Children’s Hospital Medical Center)

  • Nagendra Monangi

    (Cincinnati Children’s Hospital Medical Center
    University of Cincinnati College of Medicine)

  • Gülay Dagdas

    (University of Vienna)

  • Nina Zupančič

    (University Medical Center Ljubljana, Department of Cardiovascular Surgery)

  • Jamie Maziarz

    (Yale University)

  • Debora Sinner

    (Cincinnati Children’s Hospital Medical Center
    University of Cincinnati College of Medicine)

  • Ge Zhang

    (Cincinnati Children’s Hospital Medical Center)

  • Günter Wagner

    (University of Vienna
    Yale University
    Yale University
    Gynecology and Reproductive Sciences, Yale School of Medicine)

  • Louis Muglia

    (Cincinnati Children’s Hospital Medical Center
    Burroughs Wellcome Fund, Research Triangle Park)

Abstract

The common human SNP rs3820282 is associated with multiple phenotypes including gestational length and likelihood of endometriosis and cancer, presenting a paradigmatic pleiotropic variant. Deleterious pleiotropic mutations cause the co-occurrence of disorders either within individuals, or across population. When adverse and advantageous effects are combined, pleiotropy can maintain high population frequencies of deleterious alleles. To reveal the causal molecular mechanisms of this pleiotropic SNP, we introduced this substitution into the mouse genome by CRISPR/Cas 9. Previous work showed that rs3820282 introduces a high-affinity estrogen receptor alpha-binding site at the Wnt4 locus. Here, we show that this mutation upregulates Wnt4 transcription in endometrial stroma, following the preovulatory estrogen peak. Effects on uterine transcription include downregulation of epithelial proliferation and induction of progesterone-regulated pro-implantation genes. We propose that these changes increase uterine permissiveness to embryo invasion, whereas they decrease resistance to invasion by cancer and endometriotic foci in other estrogen-responsive tissues.

Suggested Citation

  • Mihaela Pavličev & Caitlin E. McDonough-Goldstein & Andreja Moset Zupan & Lisa Muglia & Yueh-Chiang Hu & Fansheng Kong & Nagendra Monangi & Gülay Dagdas & Nina Zupančič & Jamie Maziarz & Debora Sinner, 2024. "A common allele increases endometrial Wnt4 expression, with antagonistic implications for pregnancy, reproductive cancers, and endometriosis," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45338-4
    DOI: 10.1038/s41467-024-45338-4
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    References listed on IDEAS

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