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Statistical Mechanics in Systems Biology: Villa Orlandi, Anacapri ~ May 29 - June 1, 2012 |
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Michele Caselle Dipartimento di Fisica, Universita' di Torino (Italy) The role and functions of microRNA-mediated circuits in the human regulatory network MicroRNAs are endogenous non-coding RNAs which negatively regulate the expression of protein-coding genes in plants and animals. They are known to play an important role in several biological processes and, together with transcription factors, form a complex and highly interconnected regulatory network. Looking at the structure of this network, it is possible to recognize a few overrepresented motifs which are expected to perform important elementary regulatory functions. Among them, a special role is played by miRNA-mediated feedforward loops in which a master transcription factor regulates a microRNA and, together with it, a set of target genes. We show analytically and through simulations that the incoherent version of this motif can couple the fine-tuning of a target protein level with an efficient noise control, thus conferring precision and stability to the overall gene expression program, especially in the presence of fluctuations in upstream regulators. Among the other results, a nontrivial prediction of our model is that the optimal attenuation of fluctuations coincides with a modest repression of the target expression. This feature is coherent with the expected fine-tuning function and in agreement with experimental observations of the actual effect of a wide class of microRNAs on the protein output of their targets. We also discuss the impact on fine tuning and noise-buffering efficiency of the cross-talk between microRNA targets (the so called "sponge effect") that naturally arises if the microRNA-mediated circuit is not considered as isolated, but embedded in a larger network of regulations. Finally as an example of our results we discuss in detail the miRNA mediated FFLs involving Myc as master Transcription factor. |
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