Overexpression of lncRNA EPB41L4A-AS1 Induces Metabolic Reprogramming in Trophoblast Cells and Placenta Tissue of Miscarriage
Overexpression of lncRNA EPB41L4A-AS1 Induces Metabolic Reprogramming in Trophoblast Cells and Placenta Tissue of Miscarriage
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DOI：
10.1016/j.omtn.2019.09.017
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发表时间：
2019-09
期刊：
影响因子：
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通讯作者：
Yuanchang Zhu;Qing Liu;Meijiang Liao;L. Diao;Tonghua Wu;Weijie Liao;Ziqiang Wang;Bing Li;Shikuan Zhang;Songmao Wang;W. Xie;Yuyang Jiang;Naihan Xu;Y. Zeng;Burton B. Yang;Yaou Zhang
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文献类型：
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作者：
Yuanchang Zhu;Qing Liu;Meijiang Liao;L. Diao;Tonghua Wu;Weijie Liao;Ziqiang Wang;Bing Li;Shikuan Zhang;Songmao Wang;W. Xie;Yuyang Jiang;Naihan Xu;Y. Zeng;Burton B. Yang;Yaou Zhang
长链非编码RNA（lncRNA）已被证明是许多人类疾病的关键调节因子。然而，很少有人知道他们对早期复发性流产（RM）的影响。本研究旨在探讨lncRNA EPB 41 L4 A-AS 1在胎盘滋养层细胞代谢重编程中的作用，探讨其可能参与RM的发病机制。通过基因芯片和GEO数据库分析，我们发现EPB 41 L4 A-AS 1在早期RM胎盘组织中表达显著增加，这种增加可能与雌二醇介导的PGC-1α上调有关。EPB 41 L4 A-AS 1过表达抑制糖酵解，但增加了胎盘代谢中对脂肪酸氧化的依赖性，并抑制了胎盘绒毛快速生长所必需的瓦尔堡效应，导致流产。机制分析表明EPB 41 L4 A-AS 1作为lncRNA通过增强VDAC 1和HIF-1α的天然反义转录物（NAT）lncRNA HIF 1A-AS 1启动子中H3 K4 me 3的水平来调节VDAC 1和HIF-1α的表达。总之，这些发现表明EPB 41 L4 A-AS 1的异常表达参与了早期RM的病因学，并且它可能是早期RM治疗的候选诊断标志和潜在治疗靶点。
Long non-coding RNAs (lncRNAs) have been shown to be crucial regulators in numerous human diseases. However, little is known about their effects on early recurrent miscarriage (RM). Here we aimed to investigate the role of lncRNA EPB41L4A-AS1 on placental trophoblast cell metabolic reprogramming, which might be involved in the pathogenesis of RM. After microarray and GEO database analyses, we found that EPB41L4A-AS1 was significantly increased in early RM placental tissue, and this increase may relate to estradiol-mediated upregulation of PGC-1α. EPB41L4A-AS1 overexpression inhibits glycolysis but increases the dependence on fatty acid oxidation in mitochondrion metabolism and suppresses the Warburg effect, which is necessary for rapid growth of the placental villus, leading to miscarriage. Mechanistic analyses demonstrated that EPB41L4A-AS1 functions as a lncRNA in the regulation of VDAC1 and HIF-1α expression through enhancement of H3K4me3 levels in the promoters of VDAC1 and HIF1A-AS1, a natural antisense transcript (NAT) lncRNA of HIF-1α. Taken together, these findings demonstrate that aberrant expression of EPB41L4A-AS1 is involved in the etiology of early RM, and it may be a candidate diagnostic hallmark and a potential therapeutic target for early RM treatment.