Persistent Wnt signaling affects IVF embryo implantation and offspring metabolism

Assisted reproductive technology (ART) is associated with increased implantation failure and subsequent metabolic abnormalities in offspring, but the underlying mechanisms remain largely elusive. Here, we reveal that persistent Wnt signaling during the peri-implantation stage may be a key obstacle to the implantation of in vitro fertilization (IVF) embryos in a mouse model. Wnt activation affects the deposition of H3K27ac and H3K27me3 on pluripotency genes and bivalent genes, respectively, leading to the abnormal naïve-primed transition and suppressing expression of Otx2 in the epiblast. Furthermore, treatment with the Wnt inhibitor IWP2 promotes the redistribution of histone modifications and gene expression of epiblast. Importantly, Wnt inhibiting significantly improves implantation and intrauterine development of IVF embryos and subsequently ameliorates offspring metabolic abnormalities. Moreover, Wnt inhibiting markedly improves human peri-implantation embryo development and facilitates the transition from a naïve pluripotency state. Our study reveals a novel mechanism underlying the prevention of IVF embryo implantation failure and metabolic disorders in offspring.