Competing endogenous RNA crosstalk at system level

Author summary Large regulatory networks integrate a huge number of molecular interactions into robust system-level outcomes. This capability can emerge even when individual interactions are weak and/or strongly heterogeneous. We show this in the context of human post-transcriptional regulation driven by microRNAs (miRNAs). These small non-coding RNAs mediate an extended network of weak cross-regulatory interactions between their targets. We characterize such a network in silico using a variety of quantitative measures. Despite their weakness, miRNA-mediated couplings constitute a highly interconnected regulatory layer with robust interaction patterns that contribute to the stabilization of expression levels and allow for tunable system-level responses to specific signals. As some of these features are encoded, to a large degree, in the network's topology, natural selection appears to have favored the evolution of this "soft mode" of cross-regulation between RNAs.