>>Published online before print May 13, 2003
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.1131959100
Biochemistry
Specificity of short interfering RNA determined through gene expression signatures
( DNA microarray | RNA interference | gene knockdown )
Dimitri Semizarov *, Leigh Frost, Aparna Sarthy, Paul Kroeger, Donald N. Halbert, and Stephen W. Fesik *
Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064
Communicated by Peter B. Dervan, California Institute of Technology, Pasadena, CA, April 3, 2003 (received for review January 31, 2003)
Short interfering RNA (siRNA) is widely used for studying gene function and holds great promise as a tool for validating drug targets and treating disease. A critical assumption in these applications is that the effect of siRNA on cells is specific, i.e., limited to the specific knockdown of the target gene. In this article, we characterize the specificity of siRNA by applying gene expression profiling. Several siRNAs were designed against different regions of the same target gene for three different targets. Their effects on cells were compared by using DNA microarrays to generate gene expression signatures. When the siRNA design and transfection conditions were optimized, the signatures for different siRNAs against the same target were shown to correlate very closely, whereas the signatures for different genes revealed no correlation. These results indicate that siRNA is a highly specific tool for targeted gene knockdown, establishing siRNA-mediated gene silencing as a reliable approach for large-scale screening of gene function and drug target validation.<<
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