MicroRNAs and the butterfly effect

MicroRNAs are nature’s dimmer switches for protein translation. When expressed in sufficient abundance, these singlestranded small RNAs bind to complementary nucleotide sequences in the 3' untranslated regions of target mRNAs and direct them to RNA-induced silencing complexes (RISCs) for translational suppression and degradation. Although much has been learned about the molecular mechanisms of microRNA activity, understanding their system-wide effects has lagged. Thus, striking end-organ phenotypes provoked by artificial manipulation and/or natural regulation of a given microRNA are not readily explained by modest in vivo suppression (typically 30–50%) of direct mRNA targets. Our laboratory has gained insight into this issue using whole-genome microRNA, mRNA and RISC sequencing to examine the global consequences of microRNAmRNA interactions in a model of stressadaptation, the early cardiac response to pressure overload: Deep sequencing identified approximately 370 cardiac-expressed microRNAs and approximately 8,500 cardiac-expressed mRNAs. Although bioinformatics has indicated that one-third of all mRNAs are potential microRNA targets, deep sequencing of mRNAs captured within microRNA RISC complexes (RISC-Seq) revealed that only ~1,200 of the 8,500 cardiac-expressed mRNAs (e.g., ~15%) were being directly targeted by cardiac microRNAs. Likewise, in our studies the steady-state abundance of > 600 cardiac microRNAs was significantly altered by acute hemodynamic stress, but only 63 (~10%) of these appeared to be directly targeted and regulated by microRNAs. Given the modest effects of microRNAs on suppression of their direct mRNA targets and the limited number of mRNAs that are directly targeted by microRNAs MicroRNAs and the butterfly effect