An ALS-associated mutation in the FUS 3'-UTR disrupts a microRNA-FUS regulatory circuitry.
An ALS-associated mutation in the FUS 3'-UTR disrupts a microRNA-FUS regulatory circuitry.
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DOI：
10.1038/ncomms5335
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发表时间：
2014-07-09
影响因子：
16.6
通讯作者：
Bozzoni, Irene
中科院分区：
文献类型：
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作者：
Dini Modigliani, Stefano;Morlando, Mariangela;Bozzoni, Irene
虽然RNA结合蛋白FUS的生理功能仍有待彻底表征，但FUS突变在肌萎缩侧索硬化症（ALS）中的病理作用已明确确立。在这里，我们发现导致蛋白质表达增加的人FUS突变，并在两名具有严重结果的ALS患者中鉴定，映射到FUS的3 '-UTR中的miR-141和miR-200 a识别的种子序列。我们证明FUS和这些microRNA通过前馈调节环连接，其中FUS上调miR-141/200 a，这反过来影响FUS蛋白质合成。我们还发现，Zeb 1，miR-141/200 a的目标和这两个microRNA的转录抑制子，是电路的一部分，并加强了它。我们的研究结果揭示了这种调节电路的失调和ALS发病机制之间可能存在的相关性，并打开了有趣的前景，在治疗这些突变通过广告修饰的microRNA。
While the physiologic functions of the RNA-binding protein FUS still await thorough characterization, the pathonegetic role of FUS mutations in amyotrophic lateral sclerosis (ALS) is clearly established. Here we find that a human FUS mutation that leads to increased protein expression, and was identified in two ALS patients with severe outcome, maps to the seed sequence recognized by miR-141 and miR-200a in the 3'-UTR of FUS. We demonstrate that FUS and these microRNAs are linked by a feed-forward regulatory loop where FUS upregulates miR-141/200a, which in turn impact FUS protein synthesis. We also show that Zeb1, a target of miR-141/200a and transcriptional repressor of these two microRNAs, is part of the circuitry and reinforces it. Our results reveal a possible correlation between deregulation of this regulatory circuit and ALS pathogenesis, and open interesting perspectives in the treatment of these mutations through ad hoc-modified microRNAs.