Triplexator: detecting nucleic acid triple helices in genomic and transcriptomic data.
Triplexator: detecting nucleic acid triple helices in genomic and transcriptomic data.
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DOI：
10.1101/gr.130237.111
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发表时间：
2012-07
期刊：
影响因子：
7
通讯作者：
Bailey TL
中科院分区：
文献类型：
--
作者：
Buske FA;Bauer DC;Mattick JS;Bailey TL
双链DNA能够通过在其大沟中容纳第三条核苷酸链而形成三螺旋结构。这种序列特异性过程提供了靶向感兴趣的基因组位点的有效机制，这对于生物技术和基因治疗应用具有重要价值。很可能自然界已经利用这种寻址系统进行基因调控，因为计算研究已经发现了各种基因组中大量的推定的三链体靶位点，特别是在基因启动子中富集。然而，为了更全面地了解三链体在体内的作用，不仅需要研究推定的靶点，还需要研究作为第三链的序列及其与预测的靶位点配对的能力。在这里，我们提出了Triplexator，第一个计算框架，它集成了三链体形成的各个方面，并通过讨论三链体形成的不同方面很重要的研究实例来展示其潜力。我们发现，染色质相关的RNA有一个显着更高的分数的序列特征能够形成三链体比预期的随机，这表明它们参与基因调控。我们还鉴定了数百个人类基因，这些基因的启动子中包含序列特征，预计能够与同一启动子内的靶点形成三链体，这表明三链体参与了基于反馈的基因调控。专注于生物技术应用，我们筛选哺乳动物基因组的高亲和力三链体靶位点，可用于靶向基因组位点特异性，并发现三链体形成提供了1300 nt的分辨率。
Double-stranded DNA is able to form triple-helical structures by accommodating a third nucleotide strand in its major groove. This sequence-specific process offers a potent mechanism for targeting genomic loci of interest that is of great value for biotechnological and gene-therapeutic applications. It is likely that nature has leveraged this addressing system for gene regulation, because computational studies have uncovered an abundance of putative triplex target sites in various genomes, with enrichment particularly in gene promoters. However, to draw a more complete picture of the in vivo role of triplexes, not only the putative targets but also the sequences acting as the third strand and their capability to pair with the predicted target sites need to be studied. Here we present Triplexator, the first computational framework that integrates all aspects of triplex formation, and showcase its potential by discussing research examples for which the different aspects of triplex formation are important. We find that chromatin-associated RNAs have a significantly higher fraction of sequence features able to form triplexes than expected at random, suggesting their involvement in gene regulation. We furthermore identify hundreds of human genes that contain sequence features in their promoter predicted to be able to form a triplex with a target within the same promoter, suggesting the involvement of triplexes in feedback-based gene regulation. With focus on biotechnological applications, we screen mammalian genomes for high-affinity triplex target sites that can be used to target genomic loci specifically and find that triplex formation offers a resolution of ∼1300 nt.