Sfmbt2 10th intron-hosted miR-466(a/e)-3p are important epigenetic regulators of Nfat5 signaling, osmoregulation and urine concentration in mice
Sfmbt2 10th intron-hosted miR-466(a/e)-3p are important epigenetic regulators of Nfat5 signaling, osmoregulation and urine concentration in mice
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DOI：
10.1016/j.bbagrm.2013.12.005
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发表时间：
2014-02-01
影响因子：
4.7
通讯作者：
Yang, James Y.
中科院分区：
文献类型：
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作者：
Luo, Yu;Liu, Ying;Yang, James Y.
sfmbt2承载的miR-466a-3p及其近亲通常是对许多有害环境刺激的反应中最显著上调或下调的mirna之一。然而，这些mirna在细胞应激反应中的确切作用尚不清楚。在这里，我们发现许多sfmbt2宿主的mirna在体外和体内都具有高度高渗应激反应。在肾髓质中，缺水诱导miR-466(a/b/c/e/p)-3p的表达改变，其模式与miR-200b-3p相似，miR-200b-3p是一种已知的渗透反应转录因子Nfat5的调节因子。值得注意的是，将mIMCD3细胞暴露于精氨酸抗利尿激素类似物的时间依赖性下调miR-466(a/b/c/e/p)-3p和miR-200b-3p的表达，这为这些渗透反应性miRNAs提供了一种新的调节机制。在培养的mIMCD3细胞中，我们进一步证明miR-466a-3p和miR-466g能够通过与Nfat5的3'UTR相互作用来靶向Nfat5。在过表达miR-466a-3p的转基因小鼠中，在肾皮质和髓质中均观察到Nfat5和许多其他渗透调节相关基因的显著下调。此外，发现miR-466a-3p的持续转基因过表达与多饮、多尿、离子稳态紊乱和肾脏形态有关。由于miR-466a-3p的成熟序列与miR-466e-3p完全等同，而miR-466a-3p的种子序列与miR-297(a/b/c)-3p、miR-466d-3p、miR-467g和miR-669d-3p完全等同，并且miR-466a-3p与miR-466(b/c/p)-3p仅在5'核苷酸上存在差异，因此我们提出miR-466a-3p及其许多近亲是小鼠肾Nfat5信号传导、渗透调节和尿浓度的重要表观遗传调控因子。(C) 2013年作者。Elsevier B.V.版权所有。
Sfmbt2-hosted miR-466a-3p and its close relatives are often among the most significantly up-regulated or down-regulated miRNAs in responses to numerous deleterious environmental stimuli. The exact roles of these miRNAs in cellular stress responses, however, are not clear. Here we showed that many Sfmbt2-hosted miRNAs were highly hypertonic stress responsive in vitro and in vivo. In renal medulla, water deprivation induced alterations in the expression of miR-466(a/b/c/e/p)-3p in a pattern similar to that of miR-200b-3p, a known regulator of osmoresponsive transcription factor Nfat5. Remarkably, exposure of mIMCD3 cells to an arginine vasopressin analog time-dependently down-regulated the expression of miR-466(a/b/c/e/p)-3p and miR-200b-3p, which provides a novel regulatory mechanism for these osmoresponsive miRNAs. In cultured mIMCD3 cells we further demonstrated that miR-466a-3p and miR-466g were capable of targeting Nfat5 by interacting with its 3'UTR. In transgenic mice overexpressing miR-466a-3p, significant down-regulation of Nfat5 and many other osmoregulation-related genes was observed in both the renal cortex and medulla. Moreover, sustained transgenic over-expression of miR-466a-3p was found to be associated with polydipsia, polyuria and disturbed ion homeostasis and kidney morphology. Since the mature sequence of miR-466a-3p is completely equivalent to that of miR-466e-3p and that the seed sequence of miR-466a-3p is completely equivalent to that of miR-297(a/b/c)-3p, miR-466d-3p, miR-467g and miR-669d-3p, and that miR-466a-3p differs from miR-466(b/c/p)-3p only in a 5' nucleotide, we propose that miR-466a-3p and many of its close relatives are important epigenetic regulators of renal Nfat5 signaling, osmoregulation and urine concentration in mice. (C) 2013 The Authors. Published by Elsevier B.V. All rights reserved.