College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China.
Department of Obstetrics and Gynecology, Reproductive Medical Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510642, China.
Proc Natl Acad Sci U S A. 2023 Jan 31;120(5):e2214684120. doi: 10.1073/pnas.2214684120. Epub 2023 Jan 24.
Embryo implantation, a crucial step in human reproduction, is tightly controlled by estrogen and progesterone (P) via estrogen receptor alpha and progesterone receptor (PGR), respectively. Here, we report that -methyladenosine (mA), the most abundant mRNA modification in eukaryotes, plays an essential role in embryo implantation through the maintenance of P signaling. Conditional deletion of methyltransferase-like 3 (), encoding the mA writer METTL3, in the female reproductive tract using a Cre mouse line with promoter () resulted in complete implantation failure due to pre-implantation embryo loss and defective uterine receptivity. Moreover, the uterus of null mice failed to respond to artificial decidualization. We further found that deletion was accompanied by a marked decrease in PGR protein expression. Mechanistically, we found that mRNA is a direct target for METTL3-mediated mA modification. A luciferase assay revealed that the mA modification in the 5' untranslated region (5'-UTR) of mRNA enhances PGR protein translation efficiency in a YTHDF1-dependent manner. Finally, we demonstrated that METTL3 is required for human endometrial stromal cell decidualization in vitro and that the METTL3-PGR axis is conserved between mice and humans. In summary, this study provides evidence that METTL3 is essential for normal P signaling during embryo implantation via mA-mediated translation control of mRNA.
胚胎着床是人类生殖过程中的一个关键步骤，它受到雌激素和孕激素（P）的严格控制，分别通过雌激素受体 alpha 和孕激素受体（PGR）来实现。在这里，我们报告说，在真核生物中最丰富的 mRNA 修饰——N6-甲基腺苷（m6A），通过维持 P 信号通路，在胚胎着床中发挥着重要作用。利用含有启动子（）的 Cre 小鼠系，在雌性生殖道中条件性敲除编码 m6A 写入酶 METTL3 的甲基转移酶样 3 ()，导致着床前胚胎丢失和子宫容受性缺陷，从而导致完全着床失败。此外，缺失 会导致子宫对人工蜕膜化反应不良。我们进一步发现，缺失伴随着 PGR 蛋白表达的显著减少。从机制上讲，我们发现 mRNA 是 METTL3 介导的 m6A 修饰的直接靶标。荧光素酶报告基因实验显示，METTL3 介导的 mRNA 5'非翻译区（5'-UTR）中的 m6A 修饰以 YTHDF1 依赖的方式增强 PGR 蛋白的翻译效率。最后，我们证明了 METTL3 在体外人子宫内膜基质细胞蜕膜化过程中是必需的，并且 METTL3-PGR 轴在小鼠和人类之间是保守的。总之，这项研究提供了证据，表明 METTL3 通过 m6A 介导的 mRNA 翻译控制在胚胎着床过程中对正常的 P 信号至关重要。
