2. Academic Validation
  3. Endometrial stromal Menin supports endometrial receptivity by maintaining homeostasis of WNT signaling pathway through H3K4me3 during WOI

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

  • Commun Biol. 2025 Jul 4;8(1):995. doi: 10.1038/s42003-025-08434-9.
Xin Xu 1,  Yichen Han 1,  Keer Jin 1,  Weina Xu 1 2,  Huanyu Zhang 3,  Yana Ma 1,  Xiangjuan Li 4,  Haibin Wang 5,  Mengying Liu 6 7 8,  Xiaona Lin 9 10 11
Affiliations

Affiliations

  • 1 Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
  • 2 Department of Obstetrics, Jiaxing Women and Children's Hospital, Wenzhou medical University, Jiaxing, China.
  • 3 Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility, Hangzhou, China.
  • 4 Department of Gynecology, Hangzhou Women's Hospital (Hangzhou Maternity and Child Health Care Hospital), Hangzhou, China.
  • 5 Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China. haibin.wang@xmu.edu.cn.
  • 6 Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China. liumy1224@163.com.
  • 7 Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility, Hangzhou, China. liumy1224@163.com.
  • 8 Department of Gynecology, Hangzhou Women's Hospital (Hangzhou Maternity and Child Health Care Hospital), Hangzhou, China. liumy1224@163.com.
  • 9 Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China. linna73@zju.edu.cn.
  • 10 Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility, Hangzhou, China. linna73@zju.edu.cn.
  • 11 Department of Gynecology, Hangzhou Women's Hospital (Hangzhou Maternity and Child Health Care Hospital), Hangzhou, China. linna73@zju.edu.cn.
PMID: 40610728 DOI: 10.1038/s42003-025-08434-9
Abstract

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.

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