PRC2-mediated H3K27me3 remodeling in the luminal epithelia ensures the epithelium transformation and normal embryo implantation

Uterine luminal epithelia (LE), the maternal cell type establishing the first contact with the blastocyst, acquire receptivity for normal embryo implantation. Highly dynamic gene expression changes occurred in uterine cells, including luminal epithelia, under the dominant control of ovarian estrogen and progesterone during a short period. Histone modification mediated epigenetic regulation, especially the repressive regulation such as H3K27me3, has not been explored during the process. In this study, we first systematically profiled genome wide H3K27me3 accumulation in LE at various critical time points during their differentiation, revealing rapid and global changes of H3K27me3 during the pre-implantation. Combined genetic and pharmacological approaches targeting the PRC2 core enzyme Ezh1/2, it was demonstrated that the defective remodeling of H3K27me3 in the pre-implantation stage derailed the differentiation of LE, resulting in aberrant uterine receptivity and implantation failure. Specially, in the absence of PRC2, the failed accumulation of H3K27me3, as revealed by the Cleavage Under Target & Tagmentation (CUT&Tag) data, led to aberrantly constitutive expression of Pgr, Gata2 and Sgk1, which has been reported to be downregulated in LE for normal uterine receptivity. These defects might converge to prevent FOXO1 from nuclear translocation to exert transcriptional regulation in the epithelia. Moreover, through combined omics data analysis, actin-associated genes, including Arpin, Tmod1, and Pdlim2, were identified as novel direct H3K27me3 target genes. The derepression of these genes impeded the morphological remodeling of LE, which was ameliorated upon treatment with the F-actin depolymerizing drug cytochalasin D. In summary, our findings elucidated the genetic mechanisms for the transcriptional silencing of key LE repressed genes via H3K27me3, thereby facilitating LE differentiation during the pre-implantation.