Département de Biochimie, Université de Montréal, Montréal, QC H3C 3J7 Canada.
Nucleic Acids Res. 2010 Jul;38(13):e140. doi: 10.1093/nar/gkq354. Epub 2010 May 7.
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.
微小 RNA（miRNAs）是一种天然存在的小 RNA，可调节多个基因的表达。miRNAs 的靶向规则基于其成熟产物与靶向基因 mRNAs 之间的序列互补性。基于我们目前对这些规则的理解，我们开发了一种算法来设计人工 miRNAs，以同时靶向一组预定的基因。为了在计算机上验证我们的算法，我们测试了已知受单个 miRNA 靶向的不同基因集。该算法在解决方案中找到了相应 miRNA 的种子，其中还包括新的人工 miRNA 序列的种子，这些序列也有可能靶向这些基因。我们还验证了一些设计用于同时靶向 E2F 家族成员的人工 miRNAs 的功能。这些人工 miRNAs 在正常人类成纤维细胞和前列腺癌细胞中复制了 E2Fs 抑制的效果，抑制了细胞增殖并诱导了细胞衰老。我们得出结论，当前基于种子序列的 miRNA 靶向规则可用于设计多靶人工 miRNAs。这种方法可能在研究和治疗方面都有应用。
