Importance of miRNA stability and alternative primary miRNA isoforms in gene regulation during Drosophila development.
Importance of miRNA stability and alternative primary miRNA isoforms in gene regulation during Drosophila development.
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DOI：
10.7554/elife.38389
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发表时间：
2018-07-19
期刊：
影响因子：
7.7
通讯作者：
Okamura K
中科院分区：
文献类型：
--
作者：
Zhou L;Lim MYT;Kaur P;Saj A;Bortolamiol-Becet D;Gopal V;Tolwinski N;Tucker-Kellogg G;Okamura K
成熟的microRNA（miRNAs）是由初级转录物（pri-miRNAs）加工而来的，其表达在转录和转录后水平受到控制。然而，多个层面的调控如何实现精准调控，仍是一个谜。利用已发表的和新的数据集，我们描绘了果蝇胚胎中成熟和pri-miRNA的时间过程，揭示了miRNA产生和降解的动态以及pri-miRNA异构体选择的动态变化。我们发现5'核苷酸影响成熟miRNAs的稳定性。此外，来自mir-309簇的miRNA的不同半衰期形成其时间表达模式，并且检测到miRNA在基因调控中的快速降解的重要性作为转录组中靶位点处的不同进化特征。最后，我们发现miR-3/-309的快速降解可能对调节平面细胞极性途径组分旺很重要。总之，这些结果表明，复杂的机制调节miRNA表达，以支持正常发育。细胞通过一种称为核糖体的复杂结构来喂养含有该蛋白质基因临时拷贝的分子，从而产生蛋白质。核糖体遵循这些分子中的编码指令来构建蛋白质。这些代码的临时副本是可重用的。即使细胞停止复制基因，它也会在短时间内继续产生蛋白质。microRNA（通常简称为miRNAs）可以关闭蛋白质的产生。这些短分子与产生蛋白质的分子的密码相结合。这使得核糖体无法读取分子，也使其成为酶破坏的目标。不同的miRNAs有不同的靶点，有助于微调蛋白质产生的时间和数量。miRNAs的产生有两个阶段。首先，细胞将基因复制成初级转录物（pri-miRNAs）。然后，它将这些分子转化为成熟的miRNA。细胞可以改变所产生的pri-miRNAs的数量，控制它们如何以及何时成熟，并改变成熟miRNAs的寿命。但是，目前还不清楚这些过程如何共同作用以实现对蛋白质生产的精细控制。最近的研究揭示了何时，何地以及有多少miRNA存在于发育中的生物体中。因此，科学家们现在可以开始了解细胞如何控制miRNA水平。在这里，Zhou，Lim等人在果蝇胚胎发育过程中的八个时间窗口创建了小RNA文库。这些文库包含存在于每个发育阶段的成熟miRNA。果蝇胚胎发育迅速，从一个受精卵到一个幼虫只需要24小时，它的基因必须迅速做出反应。当与现有的数据集相结合时，新数据揭示了成熟和pri-miRNAs如何随着苍蝇胚胎发育而变化。许多miRNA基因紧密地排列在一起，在果蝇基因组中形成簇。然而，果蝇胚胎并不是一次制造出所有的基因，而是一组一组地复制它们。因此，随着开发的进展，不同的miRNAs组开始使用。为了实现这一目标，细胞在不同的时间复制了簇的不同部分，并改变了它们处理pri-miRNAs的方式。来自同一簇的miRNAs持续不同的时间长度，细胞迅速破坏不需要的成熟miRNAs。这些机制共同塑造了每一组不同miRNA的时间和组成。了解miRNAs的控制是了解细胞如何调节其基因的重要一步。人类基因组中有成千上万的miRNA基因，如果不能控制它们，可能会导致人类疾病，包括癌症。未来的研究可以通过对苍蝇的其他组织或其他生物体（包括人类）的组织进行采样来扩展这项工作。
Mature microRNAs (miRNAs) are processed from primary transcripts (pri-miRNAs), and their expression is controlled at transcriptional and post-transcriptional levels. However, how regulation at multiple levels achieves precise control remains elusive. Using published and new datasets, we profile a time course of mature and pri-miRNAs in Drosophila embryos and reveal the dynamics of miRNA production and degradation as well as dynamic changes in pri-miRNA isoform selection. We found that 5’ nucleotides influence stability of mature miRNAs. Furthermore, distinct half-lives of miRNAs from the mir-309 cluster shape their temporal expression patterns, and the importance of rapid degradation of the miRNAs in gene regulation is detected as distinct evolutionary signatures at the target sites in the transcriptome. Finally, we show that rapid degradation of miR-3/–309 may be important for regulation of the planar cell polarity pathway component Vang. Altogether, the results suggest that complex mechanisms regulate miRNA expression to support normal development. Cells produce proteins by feeding molecules that contain temporary copies of the gene for that protein through a complex structure called a ribosome. The ribosome follows the coded instructions in these molecules to build the protein. These temporary copies of the code are reusable. Even if the cell stops copying a gene it will continue to produce the protein for a short time. MicroRNAs (often shortened to just miRNAs) can switch protein production off. These are short molecules that stick to the code of the protein-producing molecules. This renders the molecules unreadable to ribosomes, and also makes it a target for destruction by enzymes. Different miRNAs have different targets, helping to fine-tune the timing and amount of protein production. There are two stages to the production of miRNAs. First, the cell copies the gene into primary transcripts (pri-miRNAs). Then, it turns these molecules into mature miRNAs. The cell can vary the number of pri-miRNAs made, control how and when they mature, and change the lifespan of the mature miRNAs. But, it is unclear how these processes all work together to achieve fine control of protein production. Recent studies have revealed when, where and how much miRNA is present in developing organisms. So, scientists are now at the point where they can start to understand how cells control miRNA levels. Here, Zhou, Lim et al. created small RNA libraries at eight time windows during the development of fruit fly embryos. The libraries contained the mature miRNAs present at each developmental stage. Fruit fly embryos develop quickly, taking only 24 hours to make a larva from a single fertilized egg, and its genes must respond quickly. When combined with existing datasets, the new data revealed how mature and pri-miRNAs change as fly embryos develop. Many miRNA genes sit close together, forming clusters in the fruit fly genome. Yet rather than make them all at once, the fly embryos often copied them in sets. So, as development progressed, different groups of miRNAs came into use. To achieve this, the cells copied different parts of the cluster at different times, and altered the way they processed the pri-miRNAs. The miRNAs from the same cluster lasted for different lengths of time, and the cells rapidly destroyed unwanted mature miRNAs. Together, these mechanisms shaped the timing and composition of each distinct set of miRNAs. Understanding the control of miRNAs is an essential step in understanding how the cell regulates its genes. There are thousands of miRNA genes in the human genome, and a failure to control them can contribute to human diseases, including cancer. Future studies could extend this work by sampling other tissues of the fly, or tissues of other organisms, including humans.