Quantitative analysis of competition in post-transcriptional regulation reveals a novel signature in target expression variation

Abstract

When small RNAs are loaded onto Argonaute proteins they can form the RNA-induced silencing complexes (RISCs), which mediate RNA interference. RISC-formation is dependent on a shared pool of Argonaute proteins and RISC loading factors, and is thus susceptible to competition among small RNAs for loading. We present a mathematical model that aims to understand how small RNA competition for the PTR resources affects target gene repression. We discuss that small RNA activity is limited by RISC-formation, RISC-degradation and the availability of Argonautes. Together, these observations explain a number of PTR saturation effects encountered experimentally. We show that different competition conditions for RISC-loading result in different signatures of PTR activity determined also by the amount of RISC-recycling taking place. In particular, we find that the small RNAs less efficient at RISC-formation, using fewer resources of the PTR pathway, can perform in the low RISC-recycling range equally well as their more effective counterparts. Additionally, we predict a novel signature of PTR in target expression levels. Under conditions of low RISC-loading efficiency and high RISC-recycling, the variation in target levels increases linearly with the target transcription rate. Furthermore, we show that RISC-recycling determines the effect that Argonaute scarcity conditions have on target expression variation. Our observations taken together offer a framework of predictions which can be used in order to infer from experimental data the particular characteristics of underlying PTR activity.