Computational design of artificial RNA molecules for gene regulation.
Computational design of artificial RNA molecules for gene regulation.
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DOI：
10.1007/978-1-4939-2291-8_25
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发表时间：
2015
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影响因子：
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通讯作者：
Ferro, Alfredo
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作者：
Lagana, Alessandro;Veneziano, Dario;Russo, Francesco;Pulvirenti, Alfredo;Giugno, Rosalba;Croce, Carlo Maria;Ferro, Alfredo
RNA干扰（RNA interference，RNAi）是基因表达调控的有力工具。小的外源性非编码RNA（ncRNA）如siRNA和shRNA是主动沉默剂，旨在以特定方式靶向和切割互补mRNA。它们被广泛和成功地用于功能研究，一些正在进行和已经完成的基于siRNA的临床试验表明，在疾病中过度表达基因的调节方面取得了令人鼓舞的结果。siRNA与miRNA（从内源基因转录的小ncRNA分子）共享其生物起源和功能的许多方面，所述小ncRNA分子能够通过抑制靶mRNA的翻译或促进其降解来抑制靶mRNA的表达。虽然siRNA和人工miRNA分子可以显著降低过表达的靶基因的表达，但癌症和其他疾病也可以由上调的miRNA引发或持续。因此，在过去的近几年中，已经开发了用于miRNA沉默的分子工具，例如siRNA和miRNA海绵。这些分子已经显示出它们在由过表达的miRNA下调的基因的去阻遏中的功效。特别地，虽然单个miRNA能够抑制单个互补miRNA，但人工海绵构建体通常含有一个或多个miRNA的一个或多个结合位点，并且通过与这些miRNA的天然靶标竞争来发挥功能。因此，天然miRNA靶标在其生理水平上重新表达。在本章中，我们回顾了最成功的siRNAs、miRNAs和miRNA海绵的计算设计方法，并描述了实现它们的最流行的工具。
RNA interference (RNAi) is a powerful tool for the regulation of gene expression. Small exogenous noncoding RNAs (ncRNAs) such as siRNA and shRNA are the active silencing agents, intended to target and cleave complementary mRNAs in a specific way. They are widely and successfully employed in functional studies, and several ongoing and already completed siRNA-based clinical trials suggest encouraging results in the regulation of overexpressed genes in disease. siRNAs share many aspects of their biogenesis and function with miRNAs, small ncRNA molecules transcribed from endogenous genes which are able to repress the expression of target mRNAs by either inhibiting their translation or promoting their degradation. Although siRNA and artificial miRNA molecules can significantly reduce the expression of overexpressed target genes, cancer and other diseases can also be triggered or sustained by upregulated miRNAs. Thus, in the past recent years, molecular tools for miRNA silencing, such as antagomiRs and miRNA sponges, have been developed. These molecules have shown their efficacy in the derepression of genes downregulated by overexpressed miRNAs. In particular, while a single antagomiR is able to inhibit a single complementary miRNA, an artificial sponge construct usually contains one or more binding sites for one or more miRNAs and functions by competing with the natural targets of these miRNAs. As a consequence, natural miRNA targets are reexpressed at their physiological level. In this chapter we review the most successful methods for the computational design of siRNAs, antagomiRs, and miRNA sponges and describe the most popular tools that implement them.