miRNA-regulated dynamics in circadian oscillator models.

Background: We have studied the dynamics of miRNA regulation in two models of circadian oscillators. miRNAs are a class of small RNA molecules (18-24 nucleotides) that are known to regulate gene expression at the post-transcriptional level by reducing the amount of proteins produced by translation. This is done either by blocking translation or by degradation of mRNAs, the latter being mainly due to the initiation of a set of processes induced by formation of the miRNA:mRNA complex. Although miRNAs are known to regulate a large number of fundamental biological processes such as growth and development, their role in the dynamics of regulation is not completely understood. In exceptional cases, in particular, they can also up-regulate gene expression.

Results: We have studied simple biological systems wherein oscillations originate from negative auto regulation of gene expression. The regulation of gene expression by miRNAs is introduced into these models and the dynamics is studied via standard stochastic simulation techniques. We find that in addition to a reduction in the amplitude of the oscillation, inclusion of miRNAs in the models has the effect of altering the frequency of oscillation and thereby regulating the dynamics of protein production.

Conclusion: miRNAs can have a profound effect on the dynamics of regulatory modules, both by control of amplitude, namely by affecting the level of gene expression, as well as by control or alteration of frequency, namely by interference with the temporal sequence of gene production or delivery. We believe that our results are valid for a variety of regulatory systems, beyond the exemplars discussed here.