Abstract
MicroRNAs form a class of short, non-coding RNA molecules which are essential for proper development in tissue-based plants and animals. To help explain their role in gene regulation, a number of mathematical and computational studies have demonstrated the potential canalizing effects of microRNAs. However, such studies have typically focused on the effects of microRNAs on only one or a few target genes. Consequently, it remains unclear how these small-scale effects add up to the experimentally observed developmental outcomes resulting from microRNA perturbation at the whole-genome level. To answer this question, we built a general computational model of cell differentiation to study the effect of microRNAs in genome-scale gene regulatory networks. Our experiments show that in large gene regulatory networks, microRNAs can control differentiation time without significantly changing steady-state gene expression profiles. This temporal regulatory role cannot be naturally replicated using protein-based transcription factors alone. While several microRNAs have been shown to regulate differentiation time in vivo, our findings provide a new explanation of how the cumulative molecular actions of individual microRNAs influence genome-scale cellular dynamics. Taken together, these results may help explain why tissue-based organisms exclusively depend on miRNA-mediated regulation, while their more primitive counterparts do not.
Highlights
MicroRNAs are a class of short, 16–22 nt single-stranded RNA molecules that typically function as repressors of gene translation
Our model does not account for the cell cycle and cell division, both of which are fundamental to stem cell identity. To address this first issue, we examine the effect of alternative initial conditions on differentiation timing (§3.1.3); incorporation of the cell cycle into our gene expression model is planned as part of a future study
The degree of miRNA–mRNA connectivity did not produce a significant change in absolute differentiation time, suggesting that on the individual gene level, whether an mRNA is or is not a target of miRNAs is more important than the precise number of miRNAs targeting it
Summary
MicroRNAs (miRNAs) are a class of short, 16–22 nt single-stranded RNA molecules that typically function as repressors of gene translation. While the precise mechanism by which they accomplish this end is still a topic of debate, our current understanding is that they bind to complementary sequences on mRNAs and act through a combination of translational inhibition and catalytic decay of their targets They make up a significant part of the gene regulatory network (GRN) of all multicellular plants and animals and act in concert with transcription factors (TFs) to allow these organisms to perform complex regulatory functions. Knockout experiments in mice and zebrafish embryos have shown that disabling the entire miRNA regulatory system leads to early developmental failure [1,2,3] Despite their importance in early development, miRNAs may not be necessary for continued development following the establishment of certain cell types and basic morphological patterns [4,5]. A major focus of recent research has been on the ways in which miRNAs provide this robustness
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