Gene autoregulation via intronic microRNAs and its functions
- Equal contributors
1 Human Genetics Foudation (HuGeF), V. Nizza 52, Torino, I-10126, Italy
2 Center for Complex Systems in Molecular Biology and Medicine, University of Torino, V. Accademia Albertina 13, I-10100 Torino, Italy
3 Genomic Physics Group, UMR 7238 CNRS “Microorganism Genomics”, Paris, 75006, France
4 Université Pierre et Marie Curie, Paris, 75006, 15 rue de L’École de Médecine, France
5 National Research Council (CNR), Institute of Informatics and Telematics (IIT) and Institute of Clinical Physiology (IFC), Laboratory for Integrative System Medicine (LISM), Via Giuseppe Moruzzi 1, Pisa, I-56124, Italy
6 IRC@C: Institute for Cancer Research at Candiolo, School of Medicine, University of Torino, Str. Prov. 142, Km. 3.95, Torino, Candiolo I-10060, Italy
7 Dipartimento di Fisica Teorica and INFN, University of Torino, V. Pietro Giuria 1Torino, I-10125, Italy
BMC Systems Biology 2012, 6:131 doi:10.1186/1752-0509-6-131Published: 10 October 2012
MicroRNAs, post-transcriptional repressors of gene expression, play a pivotal role in gene regulatory networks. They are involved in core cellular processes and their dysregulation is associated to a broad range of human diseases. This paper focus on a minimal microRNA-mediated regulatory circuit, in which a protein-coding gene (host gene) is targeted by a microRNA located inside one of its introns.
Autoregulation via intronic microRNAs is widespread in the human regulatory network, as confirmed by our bioinformatic 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 host gene expression, can induce complex responses implementing adaptation and Weber’s law, and efficiently filters fluctuations propagating from the upstream network to the host gene. A fine-tuning of the circuit parameters can optimize each of these functions. Interestingly, they are all related to gene expression homeostasis, in agreement with the increasing evidence suggesting a role of microRNA regulation in conferring robustness to biological processes. In addition to model analysis, we present a list of bioinformatically predicted candidate circuits in human for future experimental tests.
The results presented here suggest a potentially relevant functional role for negative self-regulation via intronic microRNAs, in particular as a homeostatic control mechanism of gene expression. Moreover, the map of circuit functions in terms of experimentally measurable parameters, resulting from our analysis, can be a useful guideline for possible applications in synthetic biology.