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Upregulation of PUM1 Expression in Preeclampsia Impairs Trophoblast Invasion by Negatively Regulating the Expression of the lncRNA HOTAIR.
Molecular Therapy ( IF 12.4 ) Pub Date : 2019-12-06 , DOI: 10.1016/j.ymthe.2019.11.025
Yan Zhang 1 , Xiao-Ying He 2 , Shi Qin 2 , Hui-Qin Mo 2 , Xiao Li 2 , Fan Wu 2 , Jing Zhang 2 , Xing Li 1 , Lin Mao 1 , Ya-Qing Peng 1 , Yu-Na Guo 2 , Yi Lin 2 , Fu-Ju Tian 2
Affiliation  

Pumilio (PUM) proteins are members of a highly conserved RNA-binding protein family that posttranscriptionally regulate gene expression in many organisms. However, their roles in the placenta are unclear. In the present study, we report the requirement for the PUM homolog 1 (PUM1) gene in preeclampsia (PE). Immunofluorescence and immunohistochemical data showed that PUM1 was highly expressed in human placental villi from women with PE compared to healthy controls (HCs). Further, PUM1 overexpression repressed, and knockdown enhanced, the invasion and proliferation of trophoblasts. Interestingly, PUM1 knockdown promoted trophoblast invasion in a villous explant culture model, while PUM1 overexpression repressed these effects. Furthermore, lncRNA transcriptome sequencing coupled with RNA immunoprecipitation (RIP) revealed that PUM1 inhibits trophoblast invasion in PE by downregulating the expression of lncRNA HOTAIR. Moreover, PUM1 regulates HOTAIR expression via a posttranscriptional mechanism. Using RNA-protein pull-down and mRNA stability assays, we identified PUM1 as a specific binding partner that decreased the half-life of HOTAIR and lowered the steady-state level of HOTAIR expression, suggesting a novel posttranscriptional regulatory mechanism. Collectively, these findings identified a novel RNA regulatory mechanism, revealing a new pathway governing the regulation of PUM1/HOTAIR in trophoblast invasion in the pathogenesis of PE.

中文翻译:

子痫前期中PUM1表达的上调通过负调控lncRNA HOTAIR的表达来损害滋养细胞的侵袭。

Pumilio(PUM)蛋白是高度保守的RNA结合蛋白家族的成员,该家族在转录后调节许多生物体中的基因表达。但是,它们在胎盘中的作用尚不清楚。在本研究中,我们报告了先兆子痫(PE)中PUM同源1(PUM1)基因的需求。免疫荧光和免疫组化数据显示,与健康对照组(HCs)相比,PE妇女在人胎盘绒毛中PUM1的表达较高。此外,PUM1的过度表达抑制了滋养细胞的侵袭和增殖,而敲低的增强了滋养细胞的侵袭和增殖。有趣的是,PUM1敲低促进了绒毛状外植体培养模型中滋养细胞的侵袭,而PUM1的过表达抑制了这些作用。此外,lncRNA转录组测序与RNA免疫沉淀(RIP)结合显示,PUM1通过下调lncRNA HOTAIR的表达来抑制PE中滋养细胞的侵袭。此外,PUM1通过转录后机制调节HOTAIR表达。使用RNA蛋白质下拉和mRNA稳定性测定法,我们确定PUM1为特异性结合伴侣,可降低HOTAIR的半衰期并降低HOTAIR表达的稳态水平,表明存在新的转录后调控机制。总的来说,这些发现确定了一种新的RNA调控机制,揭示了在PE发病机理中,调控PUM1 / HOTAIR在滋养细胞入侵中调控的新途径。使用RNA蛋白质下拉和mRNA稳定性测定法,我们确定PUM1为特异性结合伴侣,可降低HOTAIR的半衰期并降低HOTAIR表达的稳态水平,表明存在新的转录后调控机制。总的来说,这些发现确定了一种新的RNA调控机制,揭示了在PE发病机理中,调控PUM1 / HOTAIR在滋养细胞入侵中调控的新途径。使用RNA蛋白质下拉和mRNA稳定性测定法,我们确定PUM1为特异性结合伴侣,可降低HOTAIR的半衰期并降低HOTAIR表达的稳态水平,表明存在新的转录后调控机制。总的来说,这些发现确定了一种新的RNA调控机制,揭示了在PE发病机理中,调控PUM1 / HOTAIR在滋养细胞入侵中调控的新途径。
更新日期:2019-12-06
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