Gene autoregulation via intronic microRNAs and its functions.

BACKGROUND: MicroRNAs, post-transcriptional repressors of gene expression, play a pivotal role in gene regulatorynetworks. They are involved in core cellular processes and their dysregulation is associated to a broad range ofhuman diseases. This paper focus on a minimal microRNA-mediated regulatory circuit, in which aprotein-coding gene (host gene) is targeted by a microRNA located inside one of its introns. RESULTS: Autoregulation via intronic microRNAs is widespread in the human regulatory network, as confirmed by ourbioinformatic analysis, and can perform several regulatory tasks despite its simple topology. Our analysis,based on analytical calculations and simulations, indicates that this circuitry alters the dynamics of the hostgene expression, can induce complex responses implementing adaptation and Weber's law, and efficientlyfilters fluctuations propagating from the upstream network to the host gene. A fine-tuning of the circuitparameters can optimize each of these functions. Interestingly, they are all related to gene expressionhomeostasis, in agreement with the increasing evidence suggesting a role of microRNA regulation inconferring robustness to biological processes. In addition to model analysis, we present a list ofbioinformatically predicted candidate circuits in human for future experimental tests. CONCLUSIONS: The results presented here suggest a potentially relevant functional role for negative self-regulation via intronicmicroRNAs, in particular as a homeostatic control mechanism of gene expression. Moreover, the map ofcircuit functions in terms of experimentally measurable parameters, resulting from our analysis, can be auseful guideline for possible applications in synthetic biology.