title: RNA-based regulation: dynamics and response to perturbations of competing RNAs.
abstract: The observation that, through a titration mechanism, microRNAs (miRNAs) can act as mediators of effective interactions among their common targets (competing endogenous RNAs or ceRNAs) has brought forward the idea (i.e., the ceRNA hypothesis) that RNAs can regulate each other in extended cross-talk networks. Such an ability might play a major role in posttranscriptional regulation to shape a cell's protein repertoire. Recent work focusing on the emergent properties of the cross-talk networks has emphasized the high flexibility and selectivity that may be achieved at stationarity. On the other hand, dynamical aspects, possibly crucial on the relevant timescales, are far less clear. We have carried out a dynamical study of the ceRNA hypothesis on a model of posttranscriptional regulation. Sensitivity analysis shows that ceRNA cross-talk is dynamically extended, i.e., it may take place on timescales shorter than those required to achieve stationarity even in cases where no cross-talk occurs in the steady state, and is possibly amplified. In addition, in the case of large, transfection-like perturbations, the system may develop a strongly nonlinear, threshold response. Finally, we show that the ceRNA effect provides a very efficient way for a cell to achieve fast positive shifts in the level of a ceRNA when necessary. These results indicate that competition for miRNAs may indeed provide an elementary mechanism to achieve system-level regulatory effects on the transcriptome over physiologically relevant timescales.
authors.affiliation: Sorbonne Universités, Pierre-and-Marie-Curie University, University Paris-VI, Institut Calcul et Simulation, Paris, France; Sorbonne Universités, Pierre-and-Marie-Curie University, University Paris-VI, Unit of Mixed Research 7238, Computational and Quantitative Biology, Paris, France; Centre National de la Recherche Scientifique, Unit of Mixed Research 7238, Computational and Quantitative Biology, Paris, France; Dipartimento di Fisica, Sapienza Universitá di Roma, Rome, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Figliuzzi
authors.affiliation: Dipartimento di Fisica, Sapienza Universitá di Roma, Rome, Italy; The Institute for Chemico-Physical Processes, National Research Council, Unità di Roma-Sapienza, Rome, Italy; Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy. Electronic address: andrea.demartino@roma1.infn.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: De Martino
authors.affiliation: Dipartimento di Fisica, Sapienza Universitá di Roma, Rome, Italy; The Institute for Chemico-Physical Processes, National Research Council, Unità di Roma-Sapienza, Rome, Italy; Istituto Nazionale di Fisica Nucleare, Sezione di Roma 1, Rome, Italy.
authors.forename: Enzo
authors.initials: E
authors.lastname: Marinari
mesh_terms: D000465:Algorithms; D007700:Kinetics; D008957:Models, Genetic; D017711:Nonlinear Dynamics; D012313:RNA / Q000737:chemistry*
chemical_list: D012313:RNA