Dysregulated DNA Methyltransferase 3A Upregulates IGFBP5 to Suppress Trophoblast Cell Migration and Invasion in Preeclampsia
Dysregulated DNA Methyltransferase 3A Upregulates IGFBP5 to Suppress Trophoblast Cell Migration and Invasion in Preeclampsia
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失调的 DNA 甲基转移酶 3A 上调 IGFBP5 以抑制先兆子痫患者的滋养层细胞迁移和侵袭。
DOI：
10.1161/hypertensionaha.116.08483
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发表时间：
2017-02-01
期刊：
影响因子：
8.3
通讯作者：
Duan, Tao
中科院分区：
文献类型：
--
作者：
Jia, Yuanhui;Li, Ting;Duan, Tao
先兆子痫是人类妊娠期间独特的多系统疾病，其影响约5%至8%的妊娠。其风险和并发症已成为孕产妇和胎儿发病率和死亡率的主要原因。尽管胎盘发育异常与DNA甲基化异常有关，被认为是导致先兆子痫的原因之一，但其潜在机制至今仍不清楚。在这里，我们发现，异常DNA甲基转移酶3A（DNMT3A）在先兆子痫中起着关键作用。我们的研究结果表明，DNMT 3A的表达和定位在先兆子痫胎盘失调。此外，DNMT3A的敲低明显抑制滋养层细胞的迁移和侵袭。从机制上讲，IGFBP5（胰岛素样生长因子结合蛋白5），作为一种抑制因子，由于启动子低甲基化而被DNMT3A减少上调。重要的是，IGFBP5下调可以挽救由DNMT3A敲低引起的缺陷，从而巩固IGFBP5在滋养层中DNMT3A下游的意义。此外，我们检测到低启动子甲基化和IGFBP5的高蛋白表达在先兆子痫胎盘的临床样本。总的来说，我们的研究表明DNMT3A和IGFBP5的失调与先兆子痫有关。因此，我们建议DNMT3A和IGFBP5可以作为潜在的标记物和临床诊断和治疗先兆子痫的目标。在线补充资料
Preeclampsia is a unique multiple system disorder during human pregnancy, which affects approximate to 5% to 8% of pregnancies. Its risks and complications have become the major causes of maternal and fetal morbidity and mortality. Although abnormal placentation to which DNA methylation dysregulation is always linked is speculated to be one of the reasons causing preeclampsia, the underlying mechanisms still remain elusive to date. Here we revealed that aberrant DNA methyltransferase 3A (DNMT3A) plays a critical role in preeclampsia. Our results show that the expression and localization of DNMT3A are dysregulated in preeclamptic placenta. Moreover, knockdown of DNMT3A obviously inhibits trophoblast cell migration and invasion. Mechanistically, IGFBP5 (insulin-like growth factor-binding protein 5), known as a suppressor, is upregulated by decreased DNMT3A because of promoter hypomethylation. Importantly, IGFBP5 downregulation can rescue the defects caused by DNMT3A knockdown, thereby, consolidating the significance of IGFBP5 in the downstream of DNMT3A in trophoblast. Furthermore, we detected low promoter methylation and high protein expression of IGFBP5 in the clinical samples of preeclamptic placenta. Collectively, our study suggests that dysregulation of DNMT3A and IGFBP5 is relevant to preeclampsia. Thus, we propose that DNMT3A and IGFBP5 can serve as potential markers and targets for the clinical diagnosis and therapy of preeclampsia. Online Data Supplement