From 1993, year of their first observation, up to now, microRNAs (miRNAs) were found to be involved in the regulation of a plethora of processes, from cellular development to proliferation, from survival to apoptosis, thus playing a central role in gene regulation both in health and disease [Bartel-2009,Cesana-2011].
The observation that miRNAs can act as mediators of effective interactions among their common targets (competing for endogenous RNAs or ceRNAs) has brought forward the idea (i.e., the ceRNA hypothesis) that RNAs can regulate each other in extended cross-talk networks. Such an ability being pivotal in post-transcriptional regulation to shape a cell¿s protein repertoire. In fact, by being able to target different RNA species with different kinetics, they can act as the mediators of an effective interaction between the RNAs, such that a change in the level of one RNA can result in an alteration of the levels of another RNA.
Furthermore, the involvement of miRNAs in peculiar motifs of the human post-transcriptional regulatory (PTR) network suggests that they actively perform noise processing in gene expression.
Recent work has characterized the emergent properties of cross-talk and noise processing in small regulatory motifs in silico [Figliuzzi-2013, Bosia-2013]. Small motifs are however embedded in large, cell-scale strongly heterogeneous networks of interactions. Perturbations could propagate across this network and affect RNAs that are topologically distant through chains of miRNA-mediated couplings, creating a collective, long-range mode of regulation characterized by strong and selective cross-talks. A quantitative appraisal of this scenario, of its evolutionary signatures and of its biological consequences is our central goal.
[Bartel. Cell-2009]
[Cesana,Cacchiarelli,Legnini,Santini,Sthandier,Chinappi,Tramontano,Bozzoni. Cell-2011]
[Figliuzzi,Marinari,De Martino. Biophysical Journal-2013]
[Bosia,Pagnani,Zecchina. PloS one-2013]
Up to now, experiments and bioinformatic analysis provided a lot of information on cells miRNA-mRNA network. As much as, theoretical models explained lots of features of miRNA-mediated regulation on specific network motifs.
Nevertheless, in spite of the large numbers of target genes predicted to be affected by miRNA loss of function, gene knockout experiments for individual miRNAs have yielded many disappointing results. Most individual miRNA mutation experiments show no evident effect on phenotype [Miska-2007]. An explanation for these results resides in the functional redundancy of many miRNAs of different families working together to co-target a given gene or set of genes, providing overlapping functions. To generate an observable effect on the phenotype level, it might be necessary to delete all miRNAs that bind the considered gene (mRNA) but also others that indirectly affect it, i.e. those being connected through a chain of miRNA-ceRNA interactions.
In fact, the crucial point is that small motifs are part of large, cell-scale networks of interactions and perturbations could in principle propagate across this network, affecting mRNAs that are topologically distant through chains of miRNA-mediated couplings.
The modelization of the genome-scale post-transcriptional regulatory network, we are proposing, would allow us to identify a collective, long-range mode of regulation characterized by strong and highly selective cross-talks and noise-buffering capabilities.
Furthermore, it has been found that human PTR network forms a great number of non-canonical and non-seed interactions, which are difficult to predict by conventional bioinformatic tools and whose role in regulation is unclear. As far as our knowledge goes, we still lack a complete modelization of a cell-scale PTR network that takes into account the novel identified binding heterogeneity and this is indeed what we aim to develop.
Finally, it has been suggested that miRNAs could have a role in enhancing evolvability. A trait that presents itself consistently among different individuals of a species in spite of environmental or genetic perturbations is favored in the evolutionary process [Hornstein - 2006].
The ability of the miRNA to compensate for otherwise elevated target protein levels could allow such mutations to accrue without selective penalty. The emergence of non-lethal mutations that give diverse phenotypes is one requirement for evolvability, the generation of genetic diversity that can be selected [Kitano - 2004]. In this way, miRNAs contribute to evolvability.
The characterization of the topological and transcriptional features of PTRN at cellular scale in terms of susceptibility functions will permit to predict the effects of perturbations/mutations on single network nodes to the overall system. This could pave the way for the identification of hidden regulative pathways inside the PTR network, with great implications both in health and disease studies.
[Miska,Alvarez-Saavedra,Abbott,Lau,Hellman,McGonagle,Bartel,Ambros,Horvitz. Plos Genetics-2007]
[Hornstein,Shomron. Nature Genetics-2006]
[Kitano. Nat Rev Genet.-2004]