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

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 ensure 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 F...