Center for Quantitative Medicine, UConn Health, Farmington, CT, USA.
The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
J R Soc Interface. 2019 Sep 27;16(158):20190437. doi: 10.1098/rsif.2019.0437. Epub 2019 Sep 25.
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 , 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.
微小 RNA 形成了一类短的、非编码 RNA 分子，它们对于组织生物的正常发育至关重要。为了帮助解释它们在基因调控中的作用，许多数学和计算研究已经证明了微小 RNA 的潜在渠道化效应。然而，这些研究通常集中在微小 RNA 对一个或几个靶基因的影响上。因此，目前尚不清楚这些小规模的效应如何累加起来，导致在全基因组水平上微小 RNA 干扰后观察到的实验发育结果。为了回答这个问题，我们构建了一个通用的细胞分化计算模型，以研究微小 RNA 在全基因组基因调控网络中的作用。我们的实验表明，在大型基因调控网络中，微小 RNA 可以控制分化时间，而不会显著改变稳态基因表达谱。这种时间调控作用不能仅使用基于蛋白质的转录因子自然复制。虽然已经有几种微小 RNA 被证明可以调节分化时间，但我们的研究结果提供了一个新的解释，即单个微小 RNA 的累积分子作用如何影响全基因组细胞动力学。总之，这些结果可能有助于解释为什么组织生物完全依赖于微小 RNA 介导的调节，而它们更原始的对应物则不依赖。
