A feedforward regulatory loop between HuR and the long noncoding RNA linc-MD1 controls early phases of myogenesis.
A feedforward regulatory loop between HuR and the long noncoding RNA linc-MD1 controls early phases of myogenesis.
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DOI：
10.1016/j.molcel.2013.12.012
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发表时间：
2014-02-06
期刊：
影响因子：
16
通讯作者：
Bozzoni, Irene
中科院分区：
文献类型：
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作者：
Legnini, Ivano;Morlando, Mariangela;Mangiavacchi, Arianna;Fatica, Alessandro;Bozzoni, Irene
肌肉特异性长链非编码RNA linc-MD1被证明在肌肉分化的早期阶段表达，并通过充当miR-133和miR-135的海绵来触发向后期阶段的转换。值得注意的是，linc-MD1也是miR-133b的宿主转录本，它们的生物发生是相互排斥的。在这里，我们描述了这种替代合成是由HuR蛋白控制的，HuR蛋白通过其结合linc-MD1和抑制Drosha切割的能力有利于linc-MD1的积累。我们发现，HuR受到miR-133的抑制控制，而linc-MD1的海绵活性在前馈正循环中巩固了HuR的表达。最后，我们发现HuR也在细胞质中起作用，通过合作募集miRNA来增强linc-MD1海绵的活性。miR-133合成的增加，主要来自两个不相关的miR-133a编码基因组位点，可能触发退出该回路并进入后期分化阶段。在肌发生过程中，linc-MD1和HuR之间存在一个前馈正回路，HuR控制着miR-133b及其宿主linc-MD1 RNA的相对生物发生。linc-MD1通过海绵吞噬miR-133，减轻其对HuR表达的抑制。细胞质HuR通过合作募集miRNA来增强linc-MD1的活性。linc-MD1和miR-133由相同的前体RNA交替加工而成。这些rna在肌肉形成的早期阶段起相反的作用。Legnini等人现在表明，RNA之间的平衡是由HuR调节的，它通过抑制前体RNA上微处理器的活性来抑制miR-133的产生。
The muscle-specific long noncoding RNA linc-MD1 was shown to be expressed during early phases of muscle differentiation and to trigger the switch to later stages by acting as a sponge for miR-133 and miR-135. Notably, linc-MD1 is also the host transcript of miR-133b, and their biogenesis is mutually exclusive. Here, we describe that this alternative synthesis is controlled by the HuR protein, which favors linc-MD1 accumulation through its ability to bind linc-MD1 and repress Drosha cleavage. We show that HuR is under the repressive control of miR-133 and that the sponging activity of linc-MD1 consolidates HuR expression in a feedforward positive loop. Finally, we show that HuR also acts in the cytoplasm, reinforcing linc-MD1 sponge activity by cooperating for miRNA recruitment. An increase in miR-133 synthesis, mainly from the two unrelated miR-133a coding genomic loci, is likely to trigger the exit from this circuitry and progression to later differentiation stages. A feedforward positive loop exists between linc-MD1 and HuR during myogenesis HuR controls the relative biogenesis of miR-133b and its host linc-MD1 RNA Linc-MD1, by sponging miR-133, alleviates its repression on HuR expression Cytoplasmic HuR reinforces linc-MD1 activity by cooperating for miRNA recruitment linc-MD1 and miR-133 are alternatively processed from the same precursor RNA. These RNAs play opposing roles in early phases of myogenesis. Legnini et al. now show that the balance between the RNAs is regulated by HuR, which inhibits generation of miR-133 by inhibiting microprocessor activity on the precursor RNA.
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