Nature2014-06-26 4:14 PM

在活体中探测RNA结构 In vivo genome-wide profiling of RNA secondary structure reveals novel regulatory features


由于是单链的,所以RNA能够通过分子间和分子内的碱基配对采取多种不同的二级结构。本期Nature上发表的三篇研究论文,让我们对RNA结构在活体中的种类、动态和功能影响有了一个深入认识。Sarah Assmann及同事对模型植物拟南芥的超过1万个转录体进行了活体RNA结构分析。他们所采用的“结构-序列”方法将活体化学(DMS)探测和下一代测序相结合,在全基因组尺度上提供单核苷酸分辨率。不同结构模式被发现与编码区域、剪接点和多腺苷酸化点相关。将这些结果与通过早先的技术获得的结果所做比较显示,虽然对一些类别的基因的预测是相当准确的,但对其他基因(如在应激反应中所涉及的基因)的预测则很差,而这可能反映了使得它们更适应那种条件的变化。Jonathan Weissman及同事也建立了一个“DMS-序列”方法,来以单核苷酸精度对酵母和哺乳动物细胞中的RNA结构进行全面监测。通过将他们的发现与非活体数据相比较,作者得出结论认为,细胞内的结构要比所预料的少。甚至热稳定的RNA结构的性质在细胞中也可以被改变,这说明了细胞过程在调控RNA结构中的重要性。 Howard Chang及同事提出一个不同的问题:RNA二级结构在相关个体中是怎样在“全转录组”层面上改变的?通过计算两个家长和他们孩子的RNA二级结构,他们发现,被转录的单核苷酸变体中大约15%影响局部二级结构。这些被称为 “RiboSNitches”的结构在某些地点被耗尽,说明在那个点上某一具体RNA结构是重要的。这项研究表明,关于RNA结构的变化(尤其是那些由遗传变异所造成的变化)会怎样改变基因表达还有很多东西需要了解。


RNA structure has critical roles in processes ranging from ligand sensing to the regulation of translation, polyadenylation and splicing. However, a lack of genome-wide in vivo RNA structural data has limited our understanding of how RNA structure regulates gene expression in living cells. Here we present a high-throughput, genome-wide in vivo RNA structure probing method, structure-seq, in which dimethyl sulphate methylation of unprotected adenines and cytosines is identified by next-generation sequencing. Application of this method to Arabidopsis thaliana seedlings yielded the first in vivo genome-wide RNA structure map at nucleotide resolution for any organism, with quantitative structural information across more than 10,000 transcripts. Our analysis reveals a three-nucleotide periodic repeat pattern in the structure of coding regions, as well as a less-structured region immediately upstream of the start codon, and shows that these features are strongly correlated with translation efficiency. We also find patterns of strong and weak secondary structure at sites of alternative polyadenylation, as well as strong secondary structure at 5′ splice sites that correlates with unspliced events. Notably, in vivo structures of messenger RNAs annotated for stress responses are poorly predicted in silico, whereas mRNA structures of genes related to cell function maintenance are well predicted. Global comparison of several structural features between these two categories shows that the mRNAs associated with stress responses tend to have more single-strandedness, longer maximal loop length and higher free energy per nucleotide, features that may allow these RNAs to undergo conformational changes in response to environmental conditions. Structure-seq allows the RNA structurome and its biological roles to be interrogated on a genome-wide scale and should be applicable to any organism.






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