Systematic discovery of structural elements governing stability of mammalian messenger RNAs.
Systematic discovery of structural elements governing stability of mammalian messenger RNAs.
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DOI：
10.1038/nature11013
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发表时间：
2012-04-08
期刊：
影响因子：
64.8
通讯作者：
Tavazoie, Saeed
中科院分区：
文献类型：
--
作者：
Goodarzi, Hani;Najafabadi, Hamed S.;Oikonomou, Panos;Greco, Todd M.;Fish, Lisa;Salavati, Reza;Cristea, Ileana M.;Tavazoie, Saeed
解码RNA中的转录后调控程序是开发细胞行为预测动力学模型这一更大目标的关键一步。尽管最近的努力，RNA调控元件的广阔前景仍然在很大程度上没有特征。一个长期存在的障碍是本地RNA二级结构的贡献，在定义相互作用的合作伙伴在各种监管的情况下，包括但不限于转录稳定性，选择性剪接和本地化。有许多文献记载的情况下，结构调控元件的存在决定了选择性剪接模式（如人心肌肌钙蛋白T）或影响RNA生物学的其他方面。因此，转录后调控程序的完整表征需要捕获由局部二级结构和潜在序列提供的信息。我们已经开发了一个计算框架的基础上上下文无关的语法和互信息，系统地探讨了巨大的空间的小结构元素，并揭示了图案，是显着的信息的全基因组测量的RNA行为。这个框架的应用，全基因组的哺乳动物mRNA的稳定性数据揭示了8个高度显着的元素与大量的结构信息，其中最强的，我们表现出在全球mRNA调控的主要作用。通过生物化学、质谱和体内结合研究，我们确定HNRPA2B1是结合该元件并稳定大量靶基因的关键调节因子。最终，我们创建了一个全球性的转录后调控图谱的基础上发现的线性和结构的顺式调控元件的身份，他们的监管相互作用和他们的目标途径。这种方法也可以用来揭示调节RNA行为其他方面的结构元件。
Decoding post-transcriptional regulatory programs in RNA is a critical step in the larger goal to develop predictive dynamical models of cellular behavior. Despite recent efforts, the vast landscape of RNA regulatory elements remain largely uncharacterized. A longstanding obstacle is the contribution of local RNA secondary structure in defining 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 (e.g. 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. We have developed 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 behavior. The application of this framework to genome-wide mammalian mRNA stability data revealed eight highly significant elements with substantial structural information, for the strongest of which we showed a major role in global mRNA regulation. Through biochemistry, mass-spectrometry, and in vivo binding studies, we identified HNRPA2B1 as the key regulator that binds this element and stabilizes a large number of its target genes. Ultimately, 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 can also be employed to reveal the structural elements that modulate other aspects of RNA behavior.
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影响因子：
16.8
作者：
通讯作者：
--
DOI：
10.1073/pnas.0803169105
发表时间：
2008-09-30
影响因子：
11.1
作者：
Rabani, Michal;Kertesz, Michael;Segal, Eran
通讯作者：
Segal, Eran
影响因子：
16
作者：
Goodarzi H;Elemento O;Tavazoie S
通讯作者：
Tavazoie S
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
4.5
作者：
Doelken, Lars;Ruzsics, Zsolt;Koszinowski, Ulrich H.
通讯作者：
Koszinowski, Ulrich H.