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

Mihaela Pavličev (Corresponding author), Caitlin E. McDonough-Goldstein, Andreja Moset Zupan, Lisa Muglia, Yueh Chiang Hu, Fansheng Kong, Nagendra Monangi, Gülay Dagdas, Nina Zupančič, Jamie Maziarz, Debora Sinner, Ge Zhang, Günter Wagner, Louis Muglia

Publications: Contribution to journalArticlePeer Reviewed

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.
Original languageEnglish
Article number1152
JournalNature Communications
Volume15
Issue number1
DOIs
Publication statusPublished - 12 Feb 2024

Austrian Fields of Science 2012

  • 301301 Human genetics
  • 106038 Reproductive biology

Keywords

  • antagonistic pleiotropy
  • Embryo Implantation/physiology
  • endometriosis
  • cancer invasion

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