Designing small multiple-target artificial RNAs.
MicroRNAs (miRNAs) are naturally occurring small RNAs that regulate the expression of several genes. MiRNAs' targeting rules are based on sequence complementarity between their mature products and targeted genes' mRNAs. Based on our present understanding of those rules, we developed an algorithm to design artificial miRNAs to target simultaneously a set of predetermined genes. To validate in silico our algorithm, we tested different sets of genes known to be targeted by a single miRNA. The algorithm finds the seed of the corresponding miRNA among the solutions, which also include the seeds of new artificial miRNA sequences potentially capable of targeting these genes as well. We also validated the functionality of some artificial miRNAs designed to target simultaneously members of the E2F family. These artificial miRNAs reproduced the effects of E2Fs inhibition in both normal human fibroblasts and prostate cancer cells where they inhibited cell proliferation and induced cellular senescence. We conclude that the current miRNA targeting rules based on the seed sequence work to design multiple-target artificial miRNAs. This approach may find applications in both research and therapeutics.
De Guire
Vincent
V
Département de Biochimie, Université de Montréal, Montréal, QC H3C 3J7 Canada.
Caron
Maxime
M
Scott
Nicolas
N
Ménard
Catherine
C
Gaumont-Leclerc
Marie-France
MF
Chartrand
Pascal
P
Major
François
F
Ferbeyre
Gerardo
G
D000465:Algorithms; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence; D050684:E2F Transcription Factors / Q000037:antagonists & inhibitors; D005786:Gene Expression Regulation; D006801:Humans; D035683:MicroRNAs / Q000737:chemistry* / Q000378:metabolism
D050684:E2F Transcription Factors; D035683:MicroRNAs
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