Kobayashi Ryosuke, Tajika Yuki, Kohmaru Junki, Morita Sumiyo, Horii Takuro, Mizukami Yoichi, Aikawa Shizu, Hirota Yasushi, Hatada Izuho
Laboratory of Genome Science, Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma University, Gunma, Japan.
Department of Anatomy, Gunma University Graduate School of Medicine, Maebashi, Japan.
Cell Death Discov. 2024 Aug 8;10(1):357. doi: 10.1038/s41420-024-02134-9.
Embryo implantation failures are a major challenge in reproductive medicine, but the underlying mechanism remains poorly understood. Successful implantation requires dynamic remodeling of the endometrium through integrated proliferation and differentiation of endometrial cells including luminal epithelial, glandular epithelial, and stromal cells. Conversely, their disruption causes infertility. Spatiotemporal control of transcription is required for these processes; however, the underlying epigenetic regulation is largely unknown. In this study, we examined expression data from the human endometrium during implantation and discovered that expression of the histone lysine methyltransferase KMT2D was significantly suppressed in patients with recurrent implantation failure. Further study revealed that uterine deletion of Kmt2d in mice caused infertility due to implantation failure. Morphological analysis discovered a reduction in the number of uterine glands and aberrant differentiation of the luminal and glandular epithelium into stratified phenotypes in Kmt2d knockout uteri. Administration of leukemia inhibitory factor protein, which is expressed in uterine glands and is essential for implantation, did not rescue implantation failure in Kmt2d knockout mice, suggesting that infertility was not solely due to uterine gland dysfunction. RNA sequencing analysis revealed that Kmt2d knockout uteri displayed suppressed expression of genes involved in ion homeostasis, which may affect the uterine luminal morphology. Our study suggests that KMT2D plays an essential role in facilitating successful embryo implantation by regulating the coordinated differentiation of endometrial cells, providing valuable insights into unexplained implantation failures in women.
胚胎着床失败是生殖医学中的一个重大挑战，但其潜在机制仍知之甚少。成功着床需要通过子宫内膜细胞（包括腔上皮细胞、腺上皮细胞和基质细胞）的整合增殖和分化对子宫内膜进行动态重塑。相反，它们的破坏会导致不孕。这些过程需要转录的时空控制；然而，潜在的表观遗传调控在很大程度上尚不清楚。在本研究中，我们检查了着床期间人类子宫内膜的表达数据，发现复发性着床失败患者中组蛋白赖氨酸甲基转移酶KMT2D的表达显著受到抑制。进一步的研究表明，小鼠子宫中Kmt2d的缺失会因着床失败而导致不孕。形态学分析发现，在Kmt2d基因敲除的子宫中，子宫腺体数量减少，腔上皮和腺上皮异常分化为分层表型。给予在子宫腺体中表达且对着床至关重要的白血病抑制因子蛋白，并不能挽救Kmt2d基因敲除小鼠的着床失败，这表明不孕不仅仅是由于子宫腺体功能障碍。RNA测序分析表明，Kmt2d基因敲除的子宫显示出参与离子稳态的基因表达受到抑制，这可能会影响子宫腔形态。我们的研究表明，KMT2D通过调节子宫内膜细胞的协调分化在促进胚胎成功着床中发挥重要作用，为女性不明原因的着床失败提供了有价值的见解。
