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

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, Ge Zhang, Günter Wagner and Louis Muglia
Additional contact information
Mihaela Pavličev: Cincinnati Children’s Hospital Medical Center
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
Fansheng Kong: Cincinnati Children’s Hospital Medical Center
Nagendra Monangi: Cincinnati Children’s Hospital Medical Center
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
Ge Zhang: Cincinnati Children’s Hospital Medical Center
Günter Wagner: University of Vienna
Louis Muglia: Cincinnati Children’s Hospital Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-45338-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45338-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-45338-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().