Crosstalk between H3K4me3 and oxidative stress is a potential target for the improvement of ART-derived embryos.

With the advent and development of assisted reproductive technology (ART), more and more people affected by infertility have been able to obtain offspring successfully. Nevertheless, various adverse outcomes have been found to be associated with ART, and mechanisms behind them are still unclear. Therefore, in this study, we examine the differences between mouse pre-implantation embryos obtained via in vitro fertilization (IVF) and in vivo fertilization (IVO) at both transcriptional and epigenetic levels. We find remarkable H3K4me3 differences at blastocyst stage, which could be ascribed to the higher oxidative stress in IVF-derived blastocysts. Intriguingly, treatment with CPI-455, the inhibitor of KDM5 that catalyzes the demethylation of H3K4, successfully rescues the H3K4me3 signatures as well as transcription levels of several genes, facilitating embryo development in vitro and improving the pregnancy outcome. Consistently, CPI-455 supplementation also enhances the formation of high-quality human embryos, emphasizing the potential clinical application of CPI-455 in human ART.