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小干扰RNA的非种子区域及其靶序列是脱靶效应的辅助决定因素。

The siRNA Non-seed Region and Its Target Sequences Are Auxiliary Determinants of Off-Target Effects.

作者信息

Kamola Piotr J, Nakano Yuko, Takahashi Tomoko, Wilson Paul A, Ui-Tei Kumiko

机构信息

Department of Surgery and Cancer, Imperial College London, London, United Kingdom.

Safety Assessment, GlaxoSmithKline R&D, Ware, Hertfordshire, United Kingdom.

出版信息

PLoS Comput Biol. 2015 Dec 11;11(12):e1004656. doi: 10.1371/journal.pcbi.1004656. eCollection 2015 Dec.

DOI:10.1371/journal.pcbi.1004656
PMID:26657993
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4676691/
Abstract

RNA interference (RNAi) is a powerful tool for post-transcriptional gene silencing. However, the siRNA guide strand may bind unintended off-target transcripts via partial sequence complementarity by a mechanism closely mirroring micro RNA (miRNA) silencing. To better understand these off-target effects, we investigated the correlation between sequence features within various subsections of siRNA guide strands, and its corresponding target sequences, with off-target activities. Our results confirm previous reports that strength of base-pairing in the siRNA seed region is the primary factor determining the efficiency of off-target silencing. However, the degree of downregulation of off-target transcripts with shared seed sequence is not necessarily similar, suggesting that there are additional auxiliary factors that influence the silencing potential. Here, we demonstrate that both the melting temperature (Tm) in a subsection of siRNA non-seed region, and the GC contents of its corresponding target sequences, are negatively correlated with the efficiency of off-target effect. Analysis of experimentally validated miRNA targets demonstrated a similar trend, indicating a putative conserved mechanistic feature of seed region-dependent targeting mechanism. These observations may prove useful as parameters for off-target prediction algorithms and improve siRNA 'specificity' design rules.

摘要

RNA干扰（RNAi）是一种用于转录后基因沉默的强大工具。然而，小干扰RNA（siRNA）引导链可能会通过与微小RNA（miRNA）沉默机制极为相似的方式，通过部分序列互补与非预期的脱靶转录本结合。为了更好地理解这些脱靶效应，我们研究了siRNA引导链各个子区域内的序列特征与其相应靶序列之间的相关性以及脱靶活性。我们的结果证实了先前的报道，即siRNA种子区域中的碱基配对强度是决定脱靶沉默效率的主要因素。然而，具有共享种子序列的脱靶转录本的下调程度不一定相似，这表明存在其他影响沉默潜力的辅助因素。在此，我们证明，siRNA非种子区域一个子区域的解链温度（Tm）及其相应靶序列的GC含量均与脱靶效应效率呈负相关。对经实验验证的miRNA靶标的分析显示出类似趋势，表明种子区域依赖性靶向机制存在一个假定的保守机制特征。这些观察结果可能作为脱靶预测算法的参数，并有助于改进siRNA“特异性”设计规则。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c72/4676691/d634c4e074fb/pcbi.1004656.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c72/4676691/ef874270e8ab/pcbi.1004656.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c72/4676691/1c4e8ed1f65f/pcbi.1004656.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c72/4676691/d74256b71d8f/pcbi.1004656.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c72/4676691/04bde7a3b52b/pcbi.1004656.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c72/4676691/d634c4e074fb/pcbi.1004656.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c72/4676691/ef874270e8ab/pcbi.1004656.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c72/4676691/1c4e8ed1f65f/pcbi.1004656.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c72/4676691/d74256b71d8f/pcbi.1004656.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c72/4676691/04bde7a3b52b/pcbi.1004656.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c72/4676691/d634c4e074fb/pcbi.1004656.g005.jpg

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