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The intriguing biology of microRNAs, small regulatory noncoding RNA molecules encoded by the genome that coordinately regulate gene expression by targeting messenger RNAs, has opened new territories for our understanding of gene regulatory circuits in cardiac homeostasis and disease. It is now estimated that the human genome may encode more than 1000 miRNAs,1,2 which may regulate up to 60% of mammalian genes, and certain miRNA species are remarkably abundant in mammalian cell types.3 On average, a single miRNA has approximately 100 target sites.4 Article, see p 521 The miRNAs perform their gene regulatory function by guiding the RNAi-induced silencing complex (RISC) to partially complementary regions in the 3′UTR region of protein coding messenger RNAs (mRNAs). Within the RISC complex, miRNAs display imperfect Watson-Crick base pairing with mRNAs, ultimately leading to suppression of gene expression primarily by mRNA decay and, to a lesser extent, translational repression.5 The most commonly accepted mechanism of miRNA targeting in metazoans involves an interaction between the 5′-end bases 2 to 7 of the miRNA, designated the miRNA “seed region,” and the 3′ untranslated region (3′-UTR) of the target mRNA.6 Whereas, occasionally, additional “compensatory” sites more toward the 3′-end of the miRNA compensate for “seed” mismatches and, more rarely, more “centered” sites are also involved in base-pairing between miRNA and mRNAs,7 these different options do occur for validated targets for one single miRNA.4 Over the past decade, deciphering the roles of individual miRNAs has relied heavily on the identification of their targets to provide mechanistic context to their cellular function. As Watson-Crick base-pairing underlies miRNA–mRNA interactions and multiple metazoan genomes are now readily available, prediction of miRNA seeds throughout the genome is a seemingly straightforward task that can be tackled by the field of bioinformatics. Parallel to the … |
