School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, Fujian, China.
Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China.
Nat Commun. 2022 Feb 22;13(1):1006. doi: 10.1038/s41467-022-28657-2.
During decidualization in rodents, uterine stroma undergoes extensive reprograming into distinct cells, forming the discrete regions defined as the primary decidual zone (PDZ), the secondary decidual zone (SDZ) and the layer of undifferentiated stromal cells respectively. Here we show that uterine deletion of Men1, a member of the histone H3K4 methyltransferase complex, disrupts the terminal differentiation of stroma, resulting in chaotic decidualization and pregnancy failure. Genome-wide epigenetic profile reveals that Men1 binding in chromatin recapitulates H3K4me3 distribution. Further transcriptomic investigation demonstrates that Men1 directly regulates the expression of PTX3, an extra-cellular trap for FGF2 in decidual cells. Decreased Ptx3 upon Men1 ablation leads to aberrant activation of ERK1/2 in the SDZ due to the unrestrained FGF2 signal emanated from undifferentiated stromal cells, which blunt BMP2 induction and decidualization. In brief, our study provides genetic and molecular mechanisms for epigenetic rewiring mediated decidual regionalization by Men1 and sheds new light on pregnancy maintenance.
在啮齿动物的蜕膜化过程中，子宫基质经历广泛的重编程，形成不同的细胞，分别形成定义明确的初级蜕膜区（PDZ）、次级蜕膜区（SDZ）和未分化基质细胞层。在这里，我们表明，组织中 Men1 的缺失（组蛋白 H3K4 甲基转移酶复合物的成员）破坏了基质的终末分化，导致混乱的蜕膜化和妊娠失败。全基因组表观遗传谱表明，Men1 在染色质上的结合再现了 H3K4me3 的分布。进一步的转录组研究表明，Men1 直接调节 PTX3 的表达，PTX3 是蜕膜细胞中 FGF2 的细胞外陷阱。Men1 缺失导致 Ptx3 减少，由于未分化基质细胞释放不受限制的 FGF2 信号，导致 SDZ 中 ERK1/2 的异常激活，从而抑制 BMP2 的诱导和蜕膜化。简而言之，我们的研究为 Men1 介导的表观遗传重排介导的蜕膜区域化提供了遗传和分子机制，并为妊娠维持提供了新的视角。
