Noise Processing by MicroRNA-Mediated Circuits: the Incoherent Feed-Forward Loop, Revisited

TL;DR

This study revisits the noise-buffering ability of the miRNA-mediated Incoherent Feed Forward Loop in gene regulation, revealing that transcriptional bursting significantly impacts its effectiveness and that direct regulation often outperforms it.

Contribution

The paper provides a detailed analysis of how transcriptional bursting affects the noise-buffering capacity of the miRNA-mediated IFFL using stochastic simulations and analytical methods.

Findings

Transcriptional bursting reduces the static noise buffering of the IFFL.

Direct transcriptional regulation often outperforms the IFFL in noise control.

Dynamical noise aspects may be more relevant than static noise reduction.

Abstract

The intrinsic stochasticity of gene expression is usually mitigated in higher eukaryotes by post-transcriptional regulation channels that stabilise the output layer, most notably protein levels. The discovery of small non-coding RNAs (miRNAs) in specific motifs of the genetic regulatory network has led to identifying noise buffering as the possible key function they exert in regulation. Recent in vitro} and in silico studies have corroborated this hypothesis. It is however also known that miRNA-mediated noise reduction is hampered by transcriptional bursting in simple topologies. Here, using stochastic simulations validated by analytical calculations based on van Kampen's expansion, we revisit the noise-buffering capacity of the miRNA-mediated Incoherent Feed Forward Loop (IFFL), a small module that is widespread in the gene regulatory networks of higher eukaryotes, in order to account for the effects of intermittency in the transcriptional activity of the modulator gene. We show that bursting considerably alters the circuit's ability to control static protein noise. By comparing with other regulatory architectures, we find that direct transcriptional regulation significantly outperforms the IFFL in a broad range of kinetic parameters. This suggests that, under pulsatile inputs, static noise reduction may be less important than dynamical aspects of noise and information processing in characterising the performance of regulatory elements.