Endometrial stromal Menin supports endometrial receptivity by maintaining homeostasis of WNT signaling pathway through H3K4me3 during WOI

• Published in: Communications biology Vol. 8; no. 1; pp. 995 - 14
• Main Authors: Xu, Xin, Han, Yichen, Jin, Keer, Xu, Weina, Zhang, Huanyu, Ma, Yana, Li, Xiangjuan, Wang, Haibin, Liu, Mengying, Lin, Xiaona
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.07.2025; Nature Publishing Group; Nature Portfolio
• Subjects: 631/337/100/2285; 692/699/2732/1577; Animals; Biomedical and Life Sciences; Cell activation; Cell differentiation; Cell growth; Chromatin; Dkk1 protein; Embryo Implantation; Embryos; Endometrium; Endometrium - cytology; Endometrium - metabolism; Epithelial cells; Female; Gene expression; Histones; Histones - metabolism; Homeostasis; Humans; Implantation; In vitro fertilization; Life Sciences; Menstruation; Methylation; Methyltransferase; Mice; Molecular modelling; Morphology; Pregnancy; Protein expression; Proteins; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Signal transduction; Stromal cells; Stromal Cells - metabolism; Transcriptomes; Wnt protein; Wnt Signaling Pathway
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-025-08434-9

Dysregulated endometrial receptivity is a well-established critical factor that contributes to recurrent implantation failure (RIF). Decidualization of stromal cells and differentiation of epithelial cells in the endometrium are crucial processes for achieving endometrial receptivity. Menin, the unique subunit of the H3K4 methyltransferase complex, exhibits cell-specific effects on gene expression through chromatin modification by histone 3 lysine 4 trimethylation (H3K4me3). We have previously reported the significant role of Menin-regulated modifications in H3K4me3 in the maintenance of early pregnancy in mice. However, the physiological function of Menin and its interaction with H3K4me3 in regulating human endometrial receptivity remain poorly understood. Here, we report that Menin expression is reduced in the endometrial stroma of RIF patients. Stromal Menin deficiency not only impairs the decidualization of stromal cells but also negatively impacts the differentiation of epithelial cells through HAND2-FGFs-FGFR axis. Transcriptome analysis reveals that MEN1 knockdown in stromal cells induces the aberrant activation of the WNT signaling pathway, and in vivo experiments show it is associated with a significant reduction in the weight of implantation sites. Mechanistically, Menin deficiency suppresses the expression of SFRP2 and DKK1 , which are negative regulators of the WNT signaling pathway, through H3K4me3. In summary, our study identifies Menin as a critical regulator of endometrium receptivity, advances our understanding of its molecular mechanisms, and highlights its potential role in the pathogenesis of RIF. Stromal Menin upregulates the expression of SFRP2 and DKK1 through H3K4me3 to limit the excessive activation of the WNT signalling pathway and support normal endometrial receptivity during window of implantation.