MicroRNAs 29b and 181a down-regulate the expression of the norepinephrine transporter and glucocorticoid receptors in PC12 cells.
MicroRNAs 29b and 181a down-regulate the expression of the norepinephrine transporter and glucocorticoid receptors in PC12 cells.
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DOI：
10.1111/jnc.13761
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发表时间：
2016-10
影响因子：
4.7
通讯作者：
Zhu MY
中科院分区：
文献类型：
--
作者：
Deng M;Tufan T;Raza MU;Jones TC;Zhu MY
MicroRNAs是一种短的非编码RNA，在转录后水平上提供对基因表达的全球调节。已经发现，这种调控在应激诱导的大脑表观遗传反应中发挥了作用。去甲肾上腺素转运体(Net)和糖皮质激素受体与应激后体内平衡的整合和调节密切相关。我们以前的研究表明，大鼠的Net mRNA和蛋白水平受到慢性应激和皮质酮的调节，皮质酮是通过糖皮质激素受体介导的。MiRNAs是否是调节这些蛋白质的中间体仍有待阐明。本研究旨在探讨miRNAs对去甲肾上腺素能神经元细胞株Net和糖皮质激素受体表达的可能调节作用。通过计算靶点预测，我们确定了几个潜在靶向Net和糖皮质激素受体的候选miRNAs。Western印迹结果显示，miR-181a和miR-29b的过表达显著抑制了PC12细胞Net的蛋白水平，同时伴随着[~3H]NE摄取和糖皮质激素受体的减少。荧光素酶分析证实，miR-181a和miR-29b都能与Net和糖皮质激素受体的3‘端非编码区结合。此外，皮质酮显著降低PC12细胞的内源性miR-29b水平，而糖皮质激素受体拮抗剂米非司酮不能逆转这一作用。这些观察结果表明，miR-181a和miR-29b在体外可以作为Net和糖皮质激素受体翻译的负调控因子。这种调节作用可能与应激诱导去甲肾上腺素能表型上调有关，这是在应激模型和抑郁症患者中观察到的现象。本研究表明，miR-29b和miR-181a这两个提供全球基因表达调控的短非编码RNA，通过与其mRNAs的3‘端非编码区结合，显著抑制了PC12细胞中去甲肾上腺素(NE)转运体和糖皮质激素受体(GR)的蛋白水平，以及NE的摄取。此外，细胞暴露于皮质酮后，miR-29b水平显著降低，这是一种不依赖GR的方式。
MicroRNAs are short non-coding RNAs that provide global regulation of gene expression at the post-transcriptional level. Such regulation has been found to play a role in stress-induced epigenetic responses in the brain. The norepinephrine transporter (NET) and glucocorticoid receptors are closely related to the homeostatic integration and regulation after stress. Our previous studies demonstrated that NET mRNA and protein levels in rats are regulated by chronic stress and by administration of corticosterone, which is mediated through glucocorticoid receptors. Whether miRNAs are intermediaries in the regulation of these proteins remains to be elucidated. The present study was undertaken to determine possible regulatory effects of miRNAs on the expression of NET and glucocorticoid receptors in the noradrenergic neuronal cell line. Using computational target prediction, we identified several candidate miRNAs potentially targeting NET and glucocorticoid receptors. Western blot results showed that overexpression of miR-181a and miR-29b significantly repressed protein levels of NET, which is accompanied by a reduced [3H] NE uptake, and glucocorticoid receptors in PC12 cells. Luciferase reporter assays verified that both miR-181a and miR-29b bind the 3’UTR of mRNA of NET and glucocorticoid receptors. Furthermore, exposure of PC12 cells to corticosterone markedly reduced the endogenous levels of miR-29b, which was not reversed by the application of glucocorticoid receptor antagonist mifepristone. These observations indicate that miR-181a and miR-29b can function as the negative regulators of NET and glucocorticoid receptor translation in vitro. This regulatory effect may be related to stress-induced upregulation of the noradrenergic phenotype, a phenomenon observed in stress models and depressive patients. This study demonstrated that miR-29b and miR-181a, two short-non-coding RNAs that provide global regulation of gene expression, markedly repressed protein levels of norepinephrine (NE) transporter and glucocorticoid receptor (GR), as well as NE uptake by binding the 3′UTR of their mRNAs in PC12 cells. Also, exposure of cells to corticosterone significantly reduced miR-29b levels through a GR-independent way.
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