The EZH2–PRC2–H3K27me3 axis governs the endometrial cell cycle and differentiation for blastocyst invasion

Abstract

Infertility occurs in 15% of couples worldwide. Recurrent implantation failure (RIF) is one of the major problems in in vitro fertilization and embryo transfer (IVF–ET) programs, and how to manage patients with RIF to achieve successful pregnancy outcomes remains unresolved. Here, a uterine polycomb repressive complex 2 (PRC2)-regulated gene network was found to control embryo implantation. Our RNA-seq analyses of the human peri-implantation endometrium obtained from patients with RIF and fertile controls revealed that PRC2 components, including its core enzyme enhancer of zeste homolog 2 (EZH2)-catalyzing H3K27 trimethylation (H3K27me3) and their target genes are dysregulated in the RIF group. Although fertility of uterine epithelium-specific knockout mice of Ezh2 (eKO mice) was normal, Ezh2-deleted mice in the uterine epithelium and stroma (uKO mice) exhibited severe subfertility, suggesting that stromal Ezh2 plays a key role in female fertility. The RNA-seq and ChIP-seq analyses revealed that H3K27me3-related dynamic gene silencing is canceled, and the gene expression of cell-cycle regulators is dysregulated in Ezh2-deleted uteri, causing severe epithelial and stromal differentiation defects and failed embryo invasion. Thus, our findings indicate that the EZH2–PRC2–H3K27me3 axis is critical to preparing the endometrium for the blastocyst invasion into the stroma in mice and humans.

Decreased NSD2 impairs stromal cell proliferation in human endometrium via reprogramming H3K36me2

“…In experiments with mice, Ezh2 deletion enhances endometrial stromal cell senescence and results in pregnancy loss ( Sirohi et al 2023 ). EZH2 was reduced in the endometrium of patients with RIF and the reduction of Ezh2 in the uterine epithelium and stroma of Ezh2-deleted mice exhibited dysregulation of cell cycle regulators and severe subfertility ( Fukui et al 2023 ). The important role of EZH2 in endometrial function suggests reduced NSD2 in the endometrium of patients with RIF may lead to endometrial dysfunction.…”

“…In the present study, we found that EZH2 and NSD2 were significantly decreased in the proliferative-phase endometrium of patients with RIF compared with those in the FER controls. The mechanism by which EZH2 regulates endometrial function is relatively clear ( Grimaldi et al 2011 , Fukui et al 2023 , Sirohi et al 2023 ), while the mechanism by which NSD2 regulates endometrial function is still unclear. Therefore, we chose NSD2 for further research.…”

The involvement of RNA N6‐methyladenosine and histone methylation modification in decidualization and endometriosis‐associated infertility

“…Two recently studies showed that adult female mice with a conditional deletion of Ezh2 in both epithelial and stromal cell of uterus result in pregnancy loss via disturbing epithelial and stromal differentiation. 69 , 70 But as the authors described in their introduction, successfully implantation depends on a series of ordered events involving embryo attachment, epithelial proliferation, stromal cell differentiation and embryo invasion. Epithelial and stromal cells do not change together during decidualization, which means the EZH2–PRC2–H3K27me3 axis may play different roles in epithelial and stromal cells, and these two types of cells also influence each other during decidualization.…”

Histone modifications in embryo implantation and placentation: insights from mouse models

“…Polycomb repressive complex 2 subunit (Ezh2), a core component of polycomb repressive complexes 2, is a histone methyltransferase that catalyzes mono-, di-, and tri-methylates histone H3 at lysine 27 (25). Given the extensive function of H3K27me3 in the process of implantation, researchers use Pgr-cre mouse model to conditional delete Ezh2 in the uterus in order to further explore the roles of H3K27me3 in implantation (26)(27)(28)(29). Osokine et al provide evidence of the critical role of Ezh2 in the regulation of wound healing responses in the decidual stromal cells during early pregnancy.…”

“…Conversely, the loss of EZH2 from the decidua leads to fibroblast activation, the induction of TGF-b target genes, and ultimately, pregnancy failure (28). H3K27me3-related gene silencing is canceled after EZH2 deletion, leading to dysregulated cell-cycle regulators expression, causing severe epithelial and stromal differentiation defects and failed embryo invasion (29). Unlike those studies using Pgr-Cre to conditional knockout Ezh2, deletion of Ezh2 using Amhr2-Cre leads to marked defects in uterine adenogenesis.…”