title: Noise processing by microRNA-mediated circuits: The Incoherent Feed-Forward Loop, revisited.
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.
authors.affiliation: The Francis Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, London WC2A 3LY, United Kingdom.
authors.forename: Silvia
authors.initials: S
authors.lastname: Grigolon
authors.affiliation: Dipartimento di Fisica e Astronomia, Università degli Studi di Firenze, Sesto Fiorentino, Italy; INFN, Sezione di Firenze, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Di Patti
authors.affiliation: Soft & Living Matter Lab, Institute of Nanotechnology (CNR-NANOTEC), Consiglio Nazionale delle Ricerche, Rome, Italy; Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy; Human Genetics Foundation, Torino, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: De Martino
authors.affiliation: Dipartimento di Fisica, Sapienza Università di Roma, Rome, Italy; INFN, Sezione di Roma, Italy.
authors.forename: Enzo
authors.initials: E
authors.lastname: Marinari
keywords: Biological sciences; Systems biology