Systematic analysis of the role of RNA-binding proteins in the regulation of RNA stability.
Systematic analysis of the role of RNA-binding proteins in the regulation of RNA stability.
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DOI：
10.1371/journal.pgen.1004684
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发表时间：
2014-11
期刊：
影响因子：
4.5
通讯作者：
Mata J
中科院分区：
文献类型：
--
作者：
Hasan A;Cotobal C;Duncan CD;Mata J
mRNA半衰期是转录特异性的，并且在真核细胞中在超过100倍的范围内变化。mRNA的稳定性可以通过序列特异性RNA结合蛋白（RBP）来调节，RBP与调控序列元件结合并调节mRNA与细胞RNA降解机制的相互作用。然而，目前还不清楚这种调节是否足以解释大范围的mRNA稳定性。为了解决这个问题，我们研究了74个粟酒裂殖酵母菌株的转录组，这些菌株在编码预测的RBP的非必需基因中携带缺失（占所有此类基因的86%）。我们确定了25株显示4至104个mRNA水平变化的菌株。这些RBP的假定靶点形成生物学上连贯的组，定义参与细胞分离、核糖体生物发生、减数分裂进程、应激反应和线粒体功能的调节子。此外，这些组中的mRNA在其编码序列和非翻译区中富含特定的序列基序，这表明它们在转录后水平上受到共调节。我们对几种RBP突变体进行了全基因组RNA稳定性测量，并证实了mRNA水平的改变是由其稳定性的变化引起的。尽管RBP调节多个调节子的衰变率，但只有16%的S。粟酒裂殖酵母的mRNA在74个缺失菌株中的任何一个中都受到影响。这表明需要其他参与者或机制来产生真核转录组的RNA半衰期的观察范围。信使RNA（mRNA）是将信息从基因（DNA）传递到蛋白质的分子。细胞含有不同数量的每种mRNA类型，这取决于它们的功能和它们的情况。每种mRNA的数量取决于其产生（转录）和降解（mRNA降解）之间的平衡。最近的研究表明，每种mRNA的降解速率对每种基因都是特异性的，但人们对这种降解是如何调控的知之甚少。在这项工作中，我们研究了一类与RNA分子结合的蛋白质（RNA结合蛋白，或RBP）在RNA衰变调控中的作用。通过系统地检查其中单个RBP已失活的细胞，我们确定了那些对RNA降解重要的RBP。我们发现了使mRNA更稳定（即它们降解得更慢）的RBP和使它们不稳定的其他RBP。这些RBP控制具有共同特征的基因的RNA，这表明它们提供了一种协调基因组功能的方法。然而，对于许多基因，我们没有发现控制其稳定性的RBP，这表明其他参与者对调节RNA降解很重要。
mRNA half-lives are transcript-specific and vary over a range of more than 100-fold in eukaryotic cells. mRNA stabilities can be regulated by sequence-specific RNA-binding proteins (RBPs), which bind to regulatory sequence elements and modulate the interaction of the mRNA with the cellular RNA degradation machinery. However, it is unclear if this kind of regulation is sufficient to explain the large range of mRNA stabilities. To address this question, we examined the transcriptome of 74 Schizosaccharomyces pombe strains carrying deletions in non-essential genes encoding predicted RBPs (86% of all such genes). We identified 25 strains that displayed changes in the levels of between 4 and 104 mRNAs. The putative targets of these RBPs formed biologically coherent groups, defining regulons involved in cell separation, ribosome biogenesis, meiotic progression, stress responses and mitochondrial function. Moreover, mRNAs in these groups were enriched in specific sequence motifs in their coding sequences and untranslated regions, suggesting that they are coregulated at the posttranscriptional level. We performed genome-wide RNA stability measurements for several RBP mutants, and confirmed that the altered mRNA levels were caused by changes in their stabilities. Although RBPs regulate the decay rates of multiple regulons, only 16% of all S. pombe mRNAs were affected in any of the 74 deletion strains. This suggests that other players or mechanisms are required to generate the observed range of RNA half-lives of a eukaryotic transcriptome. Messenger RNAs (mRNAs) are the molecules that relay the information from genes (DNA) to proteins. Cells contain different amounts of each mRNA type depending on their function and their situation. The quantity of each mRNA depends on the balance between its production (transcription) and its degradation (mRNA decay). Recent studies have shown that the rate at which each mRNA is degraded is specific for every gene, but little is known about how this is regulated. In this work, we look at the role of a class of proteins that bind to RNA molecules (RNA-binding proteins, or RBPs) in the regulation of RNA decay. By systematically examining cells in which a single RBP has been inactivated we identify those that are important for RNA degradation. We found RBPs that make mRNAs more stable (that is, they are degraded more slowly) and others that make them unstable. These RBPs control the RNAs of genes with common features, suggesting that they provide a way of coordinating the function of groups of genes. However, for many genes we did not find RBPs that control their stability, indicating that other players are important to regulate RNA degradation.
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