The Attenuation of Trophoblast Invasion Caused by the Downregulation of EZH2 Is Involved in the Pathogenesis of Human Recurrent Miscarriage
The Attenuation of Trophoblast Invasion Caused by the Downregulation of EZH2 Is Involved in the Pathogenesis of Human Recurrent Miscarriage
复制标题
EZH2下调引起的滋养层侵袭减弱与人类复发性流产的发病机制有关。
DOI：
10.1016/j.omtn.2018.12.011
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发表时间：
2019-03-01
影响因子：
8.8
通讯作者：
Chen, Zi-Jiang
中科院分区：
文献类型：
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作者：
Lv, Shijian;Wang, Na;Chen, Zi-Jiang
复发性流产(RM)目前被定义为临床确定的宫内妊娠的两次或两次以上的丢失。尽管进行了多年的研究，但对于患者和内科医生来说，RM仍然是一个令人沮丧的临床挑战，其病因仍然知之甚少。越来越多的证据表明，表观遗传修饰参与了早期胚胎发育，表观遗传模式缺陷有助于RM的发展。在这里，我们研究了ZAST同源增强子2(EZH2)在RM发病机制中的作用，发现与对照绒毛相比，RM患者绒毛中EZH2的表达显著降低。EZH2促进滋养层细胞侵袭。此外，EZH2还可通过表观遗传沉默CDX1促进上皮细胞向间充质细胞的转化。染色质免疫沉淀(ChIP)-PCR和双荧光素酶报告分析均表明，EZH2通过直接与其启动子区域结合，然后三甲基化组蛋白3-赖氨酸27来抑制CDX1的转录。此外，我们发现被广泛用于治疗流产和红斑狼疮的黄体酮通过细胞外信号调节激酶(ERK1/2)途径增加EZH2的表达。这些结果表明，EZH2可能作为表观遗传因子调节滋养层细胞的侵袭，提示EZH2可能是治疗RM的潜在靶点。
Recurrent miscarriage (RM) is currently defined as two or more losses of a clinically established intrauterine pregnancy. Despite years of research, RM continues to be a clinically frustrating challenge for patients and physicians, and its etiology remains poorly understood. Accumulating evidence has suggested that epigenetic modifications are involved in early embryogenesis, and defects in epigenetic patterning contribute to the development of RM. Here, we studied the role of enhancer of zeste homolog 2 (EZH2) in the pathogenesis of RM and found that the EZH2 expression was significantly decreased in the villi from women with RM compared with that in control villi. EZH2 promoted the invasion of trophoblast cells. Moreover, EZH2 could promote epithelial-mesenchymal transition by epigenetically silencing CDX1. Both chromatin immunoprecipitation (ChIP)-PCR and dual-luciferase report assays demonstrated that EZH2 repressed CDX1 transcription via direct binding to its promoter region and then trimethylating Histone3-Lysine27. Furthermore, we discovered that progesterone, which is used extensively in the treatment of miscarriage and RM, increased the expression of EZH2 via the extracellular signaling-regulated kinase (ERK1/2) pathway. These findings revealed that EZH2 may regulate trophoblast invasion as an epigenetic factor, suggesting that EZH2 might be a potential therapeutic target for RM.