Quantitative analysis of competition in posttranscriptional 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 (RNAi). RISC-formation is dependent on a shared pool of Argonaute proteins and RISC-loading factors, and is susceptible to competition among small RNAs. We present a mathematical model that aims to understand how small RNA competition for RISC-formation affects target gene repression. We discuss that small RNA activity is limited by RISC-formation, RISC-degradation, and the availability of Argonautes. We show that different competition conditions for RISC-loading result in different signatures of RNAi determined also by the amount of RISC-recycling taking place. In particular, we find that the small RNAs, although less efficient at RISC-formation, can perform in the low RISC-recycling range as well as their more effective counterparts. Additionally, we predict that 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 that can be used to infer from data the particular characteristics of underlying RNAi activity.