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Systematic discovery of structural elements governing stability of mammalian messenger RNAs

机译:系统发现控制哺乳动物信使RNA稳定性的结构元件

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摘要

Decoding post-transcriptional regulatory programs in RNA is a critical step towards the larger goal of developing predictive dynamical models of cellular behaviour. Despite recent efforts, the vast landscape of RNA regulatory elements remains largely uncharacterized. A long-standing obstacle is the contribution of local RNA secondary structure to the definition of interaction partners in a variety of regulatory contexts, including-but not limited to-transcript stability, alternative splicing and localization. There are many documented instances where the presence of a structural regulatory element dictates alternative splicing patterns (for example, human cardiac troponin T) or affects other aspects of RNA biology. Thus, a full characterization of post-transcriptional regulatory programs requires capturing information provided by both local secondary structures and the underlying sequence. Here we present a computational framework based on context-free grammars and mutual information that systematically explores the immense space of small structural elements and reveals motifs that are significantly informative of genome-wide measurements of RNA behaviour. By applying this framework to genome-wide human mRNA stability data, we reveal eight highly significant elements with substantial structural information, for the strongest of which we show a major role in global mRNA regulation. Through biochemistry, mass spectro-metry and in vivo binding studies, we identified human HNRPA2B1 (heterogeneous nuclear ribonucleoprotein A2/B1, also known as HNRNPA2B1) as the key regulator that binds this element and stabilizes a large number of its target genes. We created a global post-transcriptional regulatory map based on the identity of the discovered linear and structural cis-regulatory elements, their regulatory interactions and their target pathways. This approach could also be used to reveal the structural elements that modulate other aspects of RNA behaviour.%二级结构或RNA内互补序列的配对,能调控影响转录产物稳定性、剪接和定位的蛋白的结合。这些效应也受所牵涉到的RNA序列的影响。Saeed Tavazoie及其同事通过计算方法来确定哪些二级结构对RNA整体行为有最大影响。这使他们能够做出一个将序列信息、二级结构、调控互动和目标通道整合起来的图件来。
机译:解码RNA中的转录后调控程序是朝着发展细胞行为的预测动力学模型这一更大目标迈出的关键一步。尽管有最近的努力,RNA调控元件的广阔前景仍未定性。一个长期的障碍是在各种调控环境中,局部RNA二级结构对相互作用伙伴定义的贡献,包括但不限于转录本稳定性,选择性剪接和定位。在许多文献中,结构调节元件的存在决定了其他剪接模式(例如,人心脏肌钙蛋白T)或影响RNA生物学的其他方面。因此,转录后调控程序的全面表征需要捕获由本地二级结构和基础序列提供的信息。在这里,我们提出了一个基于上下文无关的语法和相互信息的计算框架,该框架系统地探索了小结构元素的巨大空间,并揭示了可对全基因组RNA行为进行全面测量的信息。通过将此框架应用于全基因组人类mRNA稳定性数据,我们揭示了具有重要结构信息的八个高度重要的元素,其中最强的元素显示了我们在全球mRNA调控中的重要作用。通过生物化学,质谱和体内结合研究,我们确定了人类HNRPA2B1(异质核核糖核蛋白A2 / B1,也称为HNRNPA2B1)是与该元素结合并稳定大量目标基因的关键调控因子。我们基于发现的线性和结构性顺式调控元件的标识,它们的调控相互作用和目标途径,创建了一个全球转录后调控图。这种方法也可用于揭示调节RNA行为其他方面的结构元素。%二级结构或RNA内互补序列的配对,能改变影响转录稳定性,剪接和定位的蛋白的结合。这些效应也Saeed Tavazoie及其同事通过计算方法来确定该二级结构对RNA整体行为有最大影响。这使他们能够做出一个将序列信息,二级结构,替代相互作用和目标通道整合起来的图件来。

著录项

  • 来源
    《Nature》 |2012年第7397期|p.264-268a2|共6页
  • 作者单位

    Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08540, USA,Department of Molecular Biology, Princeton University, Princeton, New Jersey 08540, USA,Department of Biochemistry and Molecular Biophysics, and Initiative in Systems Biology, Columbia University, New York, New York 10032, USA;

    Institute of Parasitology, McGill University, Montreal, Quebec H3G1Y6, Canada,McGill Centre for Bioinformatics, McGill University, Montreal, Quebec H3G1Y6, Canada,The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada;

    Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08540, USA,Department of Molecular Biology, Princeton University, Princeton, New Jersey 08540, USA,Department of Biochemistry and Molecular Biophysics, and Initiative in Systems Biology, Columbia University, New York, New York 10032, USA;

    Department of Molecular Biology, Princeton University, Princeton, New Jersey 08540, USA;

    Iaboratory of Systems Cancer Biology, Rockefeller University, New York, New York 10065, USA;

    Institute of Parasitology, McGill University, Montreal, Quebec H3G1Y6, Canada,McGill Centre for Bioinformatics, McGill University, Montreal, Quebec H3G1Y6, Canada,Department of Biochemistry, McGill University, Montreal, Quebec H3G1Y6, Canada;

    Department of Molecular Biology, Princeton University, Princeton, New Jersey 08540, USA;

    Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08540, USA,Department of Molecular Biology, Princeton University, Princeton, New Jersey 08540, USA,Department of Biochemistry and Molecular Biophysics, and Initiative in Systems Biology, Columbia University, New York, New York 10032, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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