Titel
A common allele increases endometrial Wnt4 expression, with antagonistic implications for pregnancy, reproductive cancers, and endometriosis
Autor*in
Caitlin E. McDonough-Goldstein
Andreja Moset Zupan
Cincinnati Children’s Hospital Medical Center
... show all
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.
Stichwort
MutagenesisUrogenital reproductive disorders
Objekt-Typ
Sprache
Englisch [eng]
Persistent identifier
phaidra.univie.ac.at/o:2082893
Erschienen in
Titel
Nature Communications
Band
15
ISSN
2041-1723
Erscheinungsdatum
2024
Publication
Springer Science and Business Media LLC
Fördergeber
Erscheinungsdatum
2024
Zugänglichkeit
Rechte
Rechteangabe
© The Author(s) 2024
Universität Wien | Universitätsring 1 | 1010 Wien | T
+43-1-4277-0