Mathematical model for autoregulated miRNA biogenesis

英文摘要：

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.