Department of Biology and Biotechnology "Charles Darwin" and IBPM, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
Department of Biology and Biotechnology "Charles Darwin" and IBPM, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy; Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Rome, Italy; Institute Pasteur Fondazione Cenci-Bolognetti, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
Mol Cell. 2014 Feb 6;53(3):506-14. doi: 10.1016/j.molcel.2013.12.012. Epub 2014 Jan 16.
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.
肌肉特异性长链非编码 RNA linc-MD1 在肌肉分化的早期阶段表达，并通过作为 miR-133 和 miR-135 的海绵体来触发向后期阶段的转变。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受 HuR 蛋白控制，该蛋白通过结合 linc-MD1 并抑制 Drosha 切割来促进 linc-MD1 的积累。我们表明 HuR 受到 miR-133 的抑制控制，并且 linc-MD1 的海绵作用在正反馈回路中巩固 HuR 的表达。最后，我们表明 HuR 也在细胞质中起作用，通过与 miRNA 募集合作增强 linc-MD1 的海绵活性。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。
