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

TL;DR

This paper presents a mathematical model analyzing how competition among small RNAs for RISC loading influences gene repression, revealing a new signature in target expression variation under specific RISC recycling conditions.

Contribution

It introduces a novel mathematical framework to understand small RNA competition in post-transcriptional regulation and predicts a new signature in target expression variation.

Findings

Different RISC-loading conditions produce distinct PTR activity signatures.

Low RISC-recycling allows less efficient small RNAs to perform similarly to more efficient ones.

Target expression variation increases linearly with transcription rate under certain conditions.

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.