Understanding epigenetic regulation in the endometrium - lessons from mouse models with implantation defects.

ABSTRACT Endometrial function, crucial for successful embryo implantation, is significantly influenced by epigenetic regulation. This review investigates the crucial roles of DNA methylation, histone modifications, chromatin remodeling, and RNA methylation in endometrial receptivity and implantation, based on a survey of recent literature on knockout mouse models with implantation defects. These models illuminate how epigenetic disruptions contribute to implantation failure, a significant human reproductive health concern. DNA methylation and histone modifications modulate endometrial receptivity by affecting gene silencing and chromatin structure, respectively. Chromatin remodeling factors also play a critical role in endometrial dynamics, influencing gene expression. Furthermore, RNA methylation emerges as critical in implantation through transcriptional and translational control. While human studies provide limited epigenetic snapshots, mouse models with suppressed epigenetic regulators reveal direct causal links between epigenetic alterations and implantation failure. Understanding these epigenetic interactions offers potential for novel therapies addressing reproductive disorders. Plain Language Summary For a pregnancy to start, an embryo must implant in the uterus. The uterus lining (endometrium) must be prepared for embryo in advance, like soil for a seed. “Epigenetic switches” control how the endometrium develops by turning genes “on” or “off.” Studying mice with implantation problems helps us understand these epigenetic switches. This review, summarizes recent research on these mice, highlighting the importance of epigenetic switches for successful implantation. These knowledges could lead to new fertility treatments. Article highlights Genetically modified mouse models are invaluable for elucidating the causal roles of epigenetic regulators in embryo implantation. DNA methylation is crucial for decidualization, with mouse models revealing dynamic changes, particularly in progesterone-responsive genes. Histone modifications, including acetylation, H3K4 methylation, and H3K27 methylation, dynamically regulate endometrial receptivity and decidualization. Chromatin remodeling complexes, especially the SWI/SNF family, are essential for endometrial function during implantation. RNA methylation, particularly m6A, plays a critical role in regulating estrogen and progesterone signaling in the murine endometrium. Future research focusing on spatiotemporal epigenetic regulation and targeted epigenetic therapies holds promise for improving reproductive outcomes. Acknowledgments The authors appreciate Dr. Makoto Sugiyama (Faculty of Veterinary Medicine, Kitasato University, Japan) and Dr. Jumpei Terakawa (Graduate School of Veterinary Science, Azabu University, Japan) for helpful discussions and suggestions. The authors utilized DeepL and Google AI Studio (Gemini 1.5 Pro) to ensure grammatical accuracy and correct spelling in the English manuscript. We sincerely regret that space constraints prevented us from citing numerous relevant references. Author contributions Ryosuke Kobayashi and Izuho Hatada wrote and revised the manuscript. Disclosure statement The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.