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 ne tune the relative concentration of their targets to any desired value. We show that this function is particularly eective when one of the targets is a Transcription Factor (TF) which regulates the other targets. This combination denes 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 ne-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 uctuations. 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 eect"). We then perform a genome wide search of these FFLs in the human regulatory network and show that they are characterized by 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 FFL 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.