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This article is part of the supplement: Selected papers from the Seventh Asia-Pacific Bioinformatics Conference (APBC 2009)

Open Access Research

A structural interpretation of the effect of GC-content on efficiency of RNA interference

Chi Y Chan1, C Steven Carmack1, Dang D Long1, Anil Maliyekkel3,2, Yu Shao1, Igor B Roninson2 and Ye Ding1*

Author Affiliations

1 Wadsworth Center, New York State Department of Health, 150 New Scotland Avenue, Albany, NY 12208, USA

2 Cancer Center, Ordway Research Institute, Albany, New York 12208, USA

3 Department of Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA

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BMC Bioinformatics 2009, 10(Suppl 1):S33 doi:10.1186/1471-2105-10-S1-S33

Published: 30 January 2009

Abstract

Background

RNA interference (RNAi) mediated by small interfering RNAs (siRNAs) or short hairpin RNAs (shRNAs) has become a powerful technique for eukaryotic gene knockdown. siRNA GC-content negatively correlates with RNAi efficiency, and it is of interest to have a convincing mechanistic interpretation of this observation. We here examine this issue by considering the secondary structures for both the target messenger RNA (mRNA) and the siRNA guide strand.

Results

By analyzing a unique homogeneous data set of 101 shRNAs targeted to 100 endogenous human genes, we find that: 1) target site accessibility is more important than GC-content for efficient RNAi; 2) there is an appreciable negative correlation between GC-content and RNAi activity; 3) for the predicted structure of the siRNA guide strand, there is a lack of correlation between RNAi activity and either the stability or the number of free dangling nucleotides at an end of the structure; 4) there is a high correlation between target site accessibility and GC-content. For a set of representative structural RNAs, the GC content of 62.6% for paired bases is significantly higher than the GC content of 38.7% for unpaired bases. Thus, for a structured RNA, a region with higher GC content is likely to have more stable secondary structure. Furthermore, by partial correlation analysis, the correlation for GC-content is almost completely diminished, when the effect of target accessibility is controlled.

Conclusion

These findings provide a target-structure-based interpretation and mechanistic insight for the effect of GC-content on RNAi efficiency.