论文标题
自动调节miRNA生物发生的数学模型
Mathematical model for autoregulated miRNA biogenesis
论文作者
论文摘要
microRNA是小型非编码核苷酸序列，在转录后水平调节靶蛋白表达。 MicroRNA的生物发生是高度调节的多步途径。 miRNA生物发生的调节可以直接由生物发生途径的成分或其他调节剂间接引起。在这项研究中，我们构建了microRNA生物发生的详细数学模型，以研究生物发生途径成分的调节作用。我们扩展了一个先前的模型，以结合DGCR8合成的微处理器调节，导出介导的转运到细胞质的转运以及由成熟的miRNA易位催化为细胞核的阳性自身调节。我们的仿真结果导致三个假设（i）生物发生在较高的导出蛋白水平下对丁香蛋白水平具有鲁棒性。 （ii）较高的miRNA转录物的形成可能导致RISC水平较低：在较低水平的导出蛋白蛋白水平上形成最佳的前体miRNA和DICER的最佳水平； （iii）成熟的miRNA易位到细胞核的阳性自身调节可以降低净功能性细胞质miRNA。在可能的情况下，我们将这些结果与模型构造或校准未使用的实验观察结果进行了比较。
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.
