A combination of transcriptional and microRNA regulation improves the stability of the relative concentrations of target genes

TL;DR

This paper demonstrates that combined transcriptional and microRNA regulation in specific feed-forward loops enhances the stability and precise control of target gene ratios, especially under stochastic fluctuations, with implications for cell cycle regulation.

Contribution

It introduces a new class of feed-forward loops where microRNAs act as master regulators, showing their effectiveness in stabilizing gene ratios and analyzing their prevalence in the human regulatory network.

Findings

FFLs with microRNA regulation can fine-tune target gene ratios.

These FFLs ensure stability against stochastic fluctuations.

Enrichment of these FFLs in key regulatory contexts like cell cycle control.

Abstract

It is well known that, under suitable conditions, microRNAs are able to fine tune the relative concentration of their targets to any desired value. We show that this function is particularly effective when one of the targets is a Transcription Factor (TF) which regulates the other targets. This combination defines a new class of feed-forward loops (FFLs) in which the microRNA plays the role of master regulator. Using both deterministic and stochastic equations we show that these FFLs are indeed able not only to fine-tune the TF/target ratio to any desired value as a function of the miRNA concentration but also, thanks to the peculiar topology of the circuit, to ensures the stability of this ratio against stochastic fluctuations. These two effects are due to the interplay between the direct transcriptional regulation and the indirect TF/Target interaction due to competition of TF and target for miRNA binding (the so called "sponge effect"). We then perform a genome wide search of these FFLs in the human regulatory network and show that they are characterizedby a very peculiar enrichment pattern. In particular they are strongly enriched in all the situations in which the TF and its target have to be precisely kept at the same concentration notwithstanding the environmental noise. As an example we discuss the FFL involving E2F1 as Transcription Factor, RB1 as target and miR-17 family as master regulator. These FFLs ensure a tight control of the E2F/RB ratio which in turns ensures the stability of the transition from the G0/G1 to the S phase in quiescent cells.