  MicroRNAs are small non-coding nucleotide sequences that regulate target
protein expression at post-transcriptional levels. Biogenesis of microRNA is a
highly regulated multi-step pathway. Regulation of miRNA biogenesis can be
caused directly by the components of the biogenesis pathway or indirectly by
other regulators. In this study, we have built a detailed mathematical model of
microRNA biogenesis to investigate the regulatory role of biogenesis pathway
components. We extended a previous model to incorporate Microprocessor
regulation of DGCR8 synthesis, exportin-mediated transport to the cytoplasm,
and positive auto-regulation catalysed by mature miRNA translocation into the
nucleus. Our simulation results lead to three hypotheses (i) Biogenesis is
robust to Dicer protein levels at higher Exportin protein levels; (ii) Higher
miRNA transcript formation may lead to lower RISC levels: an optimal level of
both precursor miRNA and Dicer is required for optimal miRNA formation at lower
levels of Exportin protein; and (iii) The positive auto-regulation by mature
miRNA translocation into the nucleus can decrease the net functional
cytoplasmic miRNA. Wherever possible, we compare these results to experimental
observations not used in the model construction or calibration.
