LIN28-let-7 axis regulates genes in immortalized human trophoblast cells by targeting the ARID3B-complex
LIN28-let-7 axis regulates genes in immortalized human trophoblast cells by targeting the ARID3B-complex
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DOI：
10.1096/fj.201900718rr
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发表时间：
2019-11-01
期刊：
影响因子：
4.8
通讯作者：
Winger, Quinton A.
中科院分区：
文献类型：
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作者：
Ali, Asghar;Anthony, Russell V.;Winger, Quinton A.
胎盘发育异常是胎儿宫内生长受限(IUGR)的主要病因之一。在这里，我们发现与正常胎盘相比，足月人IUGR中Lin28a和Lin28b显著降低，而致死7(let-7)microRNAs(MiRNAs)显著升高。我们假设let-7 miRNAs通过靶向富含AT的相互作用结构域(ARID)-3B复合体来调控已知对人类胎盘发育重要的基因[高迁移率组AT-钩子1(HMGA1)、转录调节因子Myc样蛋白(c-myc)、血管内皮生长因子A(VEGF-A)和Wnt家族成员1(WNT1)]。具有Lin28a和Lin28b基因敲除(DKO)的ACh-3P细胞显著增加let-7 miRNAs，导致ARID3A、ARID3B和赖氨酸去甲基酶4C(KDM4C)显著降低。同样，过表达Lin28a和Lin28b(DKIs)的Sw.71细胞显著减少let-7 miRNAs，导致ARID3A、ARID3B和KDM4C显著增加。在ACH-3P细胞中，ARID3A、ARID3B和KDM4C形成三蛋白复合体[包括ARID3A、ARID3B和KDM4C的三蛋白复合体(ARID3B-复合体)]，它结合HMGA1、c-MYC、VEGF-A和WNT1的启动子区域。ACH-3P细胞中的ARID3B基因敲除破坏了ARID3B-复合体，导致HMGA1、c-MYC、VEGF-A和WNT1显著减少。DKO显著减少，而DKIs HMGA1、c-MYC、VEGF-A和WNT1显著增加，这可能是由于ARID3B-复合体的调节。这是第一个研究表明ARID3B-复合体对永生化的人滋养层细胞中let-7靶标的调节。
Abnormal placental development is one of the main etiological factors for intrauterine growth restriction (IUGR). Here, we show that LIN28A and LIN28B are significantly lower and lethal-7 (let-7) microRNAs (miRNAs) significantly higher in term human IUGR vs. normal placentas. We hypothesize that let-7 miRNAs regulate genes with known importance for human placental development [high-mobility group AT-hook 1 (HMGA1), transcriptional regulator Myc-like (c-myc), vascular endothelial growth factor A (VEGF-A), and Wnt family member 1 (WNT1)] by targeting the AT-rich interacting domain (ARID)-3B complex. ACH-3P cells with LIN28A and LIN28B knockout (DKOs) significantly increased let-7 miRNAs, leading to significantly decreased ARID3A, ARID3B, and lysine demethylase 4C (KDM4C). Similarly, Sw.71 cells overexpressing LIN28A and LIN28B (DKIs) significantly decreased let-7 miRNAs, leading to significantly increased ARID3A, ARID3B, and KDM4C. In ACH-3P cells, ARID3A, ARID3B, and KDM4C make a triprotein complex [triprotein complex comprising ARID3A, ARID3B, and KDM4C (ARID3B-complex)] that binds the promoter regions of HMGA1, c-MYC, VEGF-A, and WNT1. ARID3B knockout in ACH-3P cells disrupted the ARID3B-complex, leading to a significant decrease in HMGA1, c-MYC, VEGF-A, and WNT1. DKOs had a significant reduction, whereas DKIs had a significant increase in HMGA1, c-MYC, VEGF-A, and WNT1, potentially due to regulation by the ARID3B-complex. This is the first study showing regulation of let-7 targets in immortalized human trophoblast cells by the ARID3B-complex.