The role of incoherent microRNA-mediated feedforward loops in noise buffering

TL;DR

This paper demonstrates that incoherent microRNA-mediated feedforward loops can effectively buffer gene expression noise, enhancing stability and precision in cellular regulation, with optimal noise reduction linked to modest target repression.

Contribution

It provides analytical and simulation evidence that incoherent feedforward loops confer noise buffering and stability, revealing a link between repression level and fluctuation attenuation.

Findings

Incoherent feedforward loops couple target regulation with noise control.

Optimal noise attenuation occurs at modest repression levels.

Cross-talk in regulatory networks influences noise-buffering efficiency.

Abstract

MicroRNAs are endogenous non-coding RNAs which negatively regulate the expression of protein-coding genes in plants and animals. They are known to play an important role in several biological processes and, together with transcription factors, form a complex and highly interconnected regulatory network. Looking at the structure of this network it is possible to recognize a few overrepresented motifs which are expected to perform important elementary regulatory functions. Among them a special role is played by the microRNA-mediated feedforward loop in which a master transcription factor regulates a microRNA and, together with it, a set of target genes. In this paper we show analytically and through simulations that the incoherent version of this motif can couple the fine-tuning of a target protein level with an efficient noise control, thus conferring precision and stability to the overall gene expression program, especially in the presence of fluctuations in upstream regulators. Among the other results, a nontrivial prediction of our model is that the optimal attenuation of fluctuations coincides with a modest repression of the target expression. This feature is coherent with the expected fine-tuning function and in agreement with experimental observations of the actual impact of a wide class of microRNAs on the protein output of their targets. Finally we describe the impact on noise-buffering efficiency of the cross-talk between microRNA targets that can naturally arise if the microRNA-mediated circuit is not considered as isolated, but embedded in a larger network of regulations.