Repression of FGF signaling is responsible for inhibition and impaired DNA methylation during early development of fertilized embryos.

Well-orchestrated epigenetic modifications during early development are essential for embryonic survival and postnatal growth. Erroneous epigenetic modifications due to environmental perturbations such as manipulation and culture of embryos during fertilization (IVF) are linked to various short- or long-term consequences. Among these, DNA methylation defects are of great concern. Despite the critical role of DNA methylation in determining embryonic development potential, the mechanisms underlying IVF-associated DNA methylation defects, however, remains largely elusive. We reported herein that repression of fibroblast growth factor (FGF) signaling as the main reason for IVF-associated DNA methylation defects. Comparative methylome analysis by postimplantation stage suggested that IVF mouse embryos undergo impaired DNA methylation during implantation stage. Further analyses indicated that , the main DNA methyltransferase, was consistently inhibited during the transition from the blastocyst to postimplantation stage (Embryonic day 7.5, E7.5). Using blastocysts and embryonic stem cells (ESCs) as the model, we showed repression of FGF signaling is responsible for inhibition and global hypomethylation during early development, and MEK/ERK-SP1 pathway plays an essential mediating role in FGF signaling-induced transcriptional activation of Supplementation of FGF2, which was exclusively produced in the maternal oviduct, into embryo culture medium significantly rescued inhibition. Our study, using mouse embryos as the model, not only identifies FGF signaling as the main target for correcting IVF-associated epigenetic errors, but also highlights the importance of oviductal paracrine factors in supporting early embryonic development and improving culture system.