Uterine luminal epithelia (LE), the first layer contacting with the blastocyst, acquire receptivity for normal embryo implantation. Besides the well-accepted transcriptional regulation dominated by ovarian estrogen and progesterone for receptivity establishment, the involvement of epigenetic mechanisms remains elusive. This study systematically profiles the transcriptome and genome-wide H3K27me3 distribution in the LE throughout the preimplantation. Combining genetic and pharmacological approaches targeting the PRC2 core enzyme Ezh1/2, we demonstrate that the defective remodeling of H3K27me3 in the preimplantation stage disrupts the differentiation of LE, and derails uterine receptivity, resulting in implantation failure. Specifically, crucial epithelial genes, Pgr, Gata2, and Sgk1, are transcriptionally silenced through de novo deposition of H3K27me3 for LE transformation, and their sustained expression in the absence of H3K27me3 synergistically confines the nuclear translocation of FOXO1. Further functional studies identify several actin-associated genes, including Arpin, Tmod1, and Pdlim2, as novel direct targets of H3K27me3. Their aberrantly elevated expression impedes the morphological remodeling of LE, a hindrance alleviated by treatment with cytochalasin D which depolymerizes F-actin. Collectively, this study uncovers a previously unappreciated epigenetic regulatory mechanism for the transcriptional silencing of key LE genes via H3K27me3, essential for LE differentiation and thus embryo implantation.

子宫腔上皮（LE）是与囊胚接触的第一层，获得正常胚胎植入的接受能力。除了公认的由卵巢雌激素和孕激素主导的接受性建立转录调控外，表观遗传机制的参与仍然难以捉摸。这项研究系统地分析了整个植入前 LE 中的转录组和全基因组 H3K27me3 分布。结合针对 PRC2 核心酶Ezh1/2的遗传和药理学方法，我们证明 H3K27me3 在植入前阶段的缺陷重塑会破坏 LE 的分化，并使子宫容受性脱轨，导致植入失败。具体来说，关键的上皮基因Pgr、Gata2和Sgk1通过 H3K27me3 从头沉积进行 LE 转化而被转录沉默，并且它们在 H3K27me3 不存在的情况下的持续表达协同限制了 FOXO1 的核转位。进一步的功能研究确定了几个肌动蛋白相关基因，包括Arpin、Tmod1和Pdlim2 ，作为 H3K27me3 的新直接靶标。它们异常升高的表达阻碍了 LE 的形态重塑，通过解聚 F-肌动蛋白的细胞松弛素 D 治疗可减轻这一障碍。总的来说，这项研究揭示了一种先前未被认识的表观遗传调控机制，该机制通过 H3K27me3 使关键 LE 基因转录沉默，这对于 LE 分化和胚胎植入至关重要。