Impact of RNA interference on gene networks

Small endogenous RNAs such as microRNAs (miRNAs) and small interfering RNAs (siRNAs) have been found to posttranscriptionally control cellular gene networks by targeting complementary mRNAs for translation impairment (miRNA) or destruction (siRNA). We have developed a computational model, coordinated to molecular and biochemical parameters of RNA interference pathways, to provide (semi-) quantitative insight into the molecular events managing siRNA-mediated gene expression silencing in native and synthetic gene networks. Based on mass-conservation principles and kinetic rate laws, we converted biochemical RNA interference pathways into a set of ordinary differential equations that describe the dynamics of siRNA-mediated translation-regulation in mammalian cells. Capitalizing on mechanistic details of synthetic transactivator operation, we wired this model into a transcription control circuitry in which the siRNA and its target mRNA are independently regulated at the transcriptional level. In this context, we studied the impact of siRNA transcription timing on the onset of target gene transcription and production kinetics of target mRNA-encoded proteins. We also simulated the rate of siRNA-induced mRNA depletion and demonstrated that the relative concentrations of interacting siRNAs/mRNAs and the number of siRNA-specific target sites on a transcript modulate (i) the rate of target mRNA disappearance, (ii) the steady-state mRNA levels and (iii) induction dynamics of mRNA-encoded protein production. As our model predictions are consistent with available biochemical parameters, extrapolations may improve our understanding of how complex regulatory gene networks are impacted by small endogenous RNAs. (c) 2006 Elsevier Inc. All rights reserved.