MicroRNAs tend to synergistically control expression of genes encoding extensively-expressed proteins in humans.

Considering complicated microRNA (miRNA) biogenesis and action mechanisms, it was thought so high energy-consuming for a cell to afford simultaneous over-expression of many miRNAs. Thus it prompts that an alternative miRNA regulation pattern on protein-encoding genes must exist, which has characteristics of energy-saving and precise protein output. In this study, expression tendency of proteins encoded by miRNAs' target genes was evaluated in human organ scale, followed by quantitative assessment of miRNA synergism. Expression tendency analysis suggests that universally expressed proteins (UEPs) tend to physically interact in clusters and participate in fundamental biological activities whereas disorderly expressed proteins (DEPs) are inclined to relatively independently execute organ-specific functions. Consistent with this, miRNAs that mainly target UEP-encoding mRNAs, such as miR-21, tend to collaboratively or even synergistically act with other miRNAs in fine-tuning protein output. Synergistic gene regulation may maximize miRNAs' efficiency with less dependence on miRNAs' abundance and overcome the deficiency that targeting plenty of genes by single miRNA makes miRNA-mediated regulation high-throughput but insufficient due to target gene dilution effect. Furthermore, our experiment verified that merely 25 nM transfection of miR-21 be sufficient to influence the overall state of various human cells. Thus miR-21 was identified as a hub in synergistic miRNA-miRNA interaction network. Our findings suggest that synergistic miRNA-miRNA interaction is an important endogenous miRNA regulation mode, which ensures adequate potency of miRNAs at low abundance, especially those implicated in fundamental biological regulation.