Induction of TGF-β receptor I expression in a DNA methylation-independent manner mediated by DNMT3A downregulation is involved in early-onset severe preeclampsia
Induction of TGF-β receptor I expression in a DNA methylation-independent manner mediated by DNMT3A downregulation is involved in early-onset severe preeclampsia
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DNMT3A 下调介导的以 DNA 甲基化独立的方式诱导 TGF-β 受体 I 表达与早发性重度子痫前期有关
DOI：
10.1096/fj.202000253rr
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发表时间：
2020-08-14
期刊：
影响因子：
4.8
通讯作者：
Ying, Hao
中科院分区：
文献类型：
--
作者：
Jia, Yuanhui;Xie, Han;Ying, Hao
先兆子痫，尤其是早发型重度先兆子痫是导致母儿发病和死亡的主要原因之一。尽管众所周知早发型重度先兆子痫的病理生理学始于异常胎盘形成和TGF-β信号传导的异常激活抑制滋养层细胞侵袭，但早发型重度先兆子痫中TGF-β信号传导失调的潜在机制至今仍不清楚。在这里，我们揭示了由DNMT 3A下调介导的TGFBR 1/TGF-β信号传导的诱导在早发性重度先兆子痫中起着关键作用。我们的研究结果表明，DNMT 3A下调提高滋养层细胞中的TGFBR 1表达。此外，抑制TGFBR 1和TGF-β/Smad信号传导可以挽救DNMT 3A敲低引起的滋养层细胞迁移和侵袭的缺陷。DNMT 3A通过募集EZH 2到TGFBR 1启动子上而不改变TGFBR 1启动子的DNA甲基化来抑制TGFBR 1转录。在人类样本中，我们检测到早发型重度子痫前期患者蜕膜包埋的绒毛外滋养细胞中DNMT 3A低表达，TGF-β 1高表达，TGF-β/Smad信号过度激活，这为DNMT 3A和TGF-β 1之间的相关性提供了临床证据。总的来说，我们的研究结果表明，DNA甲基化非依赖性诱导的TGFBR 1介导的DNMT 3A下调是相关的早发性重度先兆子痫的发展。
Preeclampsia, especially early-onset severe preeclampsia is one of the leading causes of maternal and fetal morbidity and mortality. Although it has been well known that the pathophysiology of early-onset severe preeclampsia begins with abnormal placentation and aberrant activation of TGF-beta signaling inhibits trophoblast cell invasion, the mechanisms underlying dysregulation of TGF-beta signaling in early-onset severe preeclampsia remain elusive to date. Here, we revealed that induction of TGFBR1/TGF-beta signaling mediated by DNMT3A downregulation plays a critical role in early-onset severe preeclampsia. Our results show that DNMT3A downregulation elevates TGFBR1 expression in trophoblast cells. Moreover, inhibition of TGFBR1 and TGF-beta/Smad signaling can rescue the deficiencies of trophoblast cell migration and invasion caused by DNMT3A knockdown. Mechanistically, DNMT3A suppresses the transcription of TGFBR1 through recruiting EZH2 to its promoter but not changing DNA methylation ofTGFBR1promoter. In human samples, we detected lowly expressed DNMT3A, highly expressed TGFBR1 and hyperactivation of TGF-beta/Smad signaling in decidua-embedded extravillous trophoblasts in early-onset severe preeclampsia, which provides the clinical evidence for the correlation between DNMT3A and TGFBR1. Collectively, our findings demonstrate that DNA methylation-independent induction of TGFBR1 mediated by DNMT3A downregulation is relevant to the development of early-onset severe preeclampsia.