Shi Fei, Yu Wenbao, Wang Xia
College of Veterinary Medicine, Sichuan Agricultural University, Ya'an 625014, Sichuan, China.
Department of Statistics, Seoul National University, Seoul 151-742, Korea.
Int J Mol Sci. 2014 Oct 21;15(10):19119-33. doi: 10.3390/ijms151019119.
miRNAs are small noncoding RNAs capable of regulating gene expression at the post-transcriptional level. A growing body of evidence demonstrated that let-7 family of miRNAs, as one of the highly conserved miRNAs, plays an important role in cell differentiation and development, as well as tumor suppressor function depending on their levels of expression. To explore the physiological significance of let-7 in regulating cell fate decisions, we present a coarse grained model of let-7 biogenesis network, in which let-7 and its regulator Lin28 inhibit mutually. The dynamics of this minimal network architecture indicates that, as the concentration of Lin28 increases, the system undergoes a transition from monostability to a bistability and then to a one-way switch with increasing strength of positive feedback of let-7, while in the absence of Lin28 inhibition, the system loses bistability. Moreover, the ratio of degradation rates of let-7 and Lin28 is critical for the switching sensitivity and resistance to stimulus fluctuations. These findings may highlight why let-7 is required for normal gene expression in the context of embryonic development and oncogenesis, which will facilitate the development of approaches to exploit this regulatory pathway by manipulating Lin28/let-7 axis for novel treatments of human diseases.
微小RNA（miRNA）是一类小的非编码RNA，能够在转录后水平调控基因表达。越来越多的证据表明，作为高度保守的miRNA之一，let-7家族的miRNA在细胞分化和发育以及肿瘤抑制功能中发挥着重要作用，这取决于它们的表达水平。为了探究let-7在调控细胞命运决定中的生理意义，我们提出了一个let-7生物发生网络的粗粒度模型，其中let-7及其调节因子Lin28相互抑制。这种最小网络结构的动力学表明，随着Lin28浓度的增加，系统经历从单稳态到双稳态的转变，然后随着let-7正反馈强度的增加转变为单向开关，而在没有Lin28抑制的情况下，系统失去双稳态。此外，let-7和Lin28的降解速率之比对于开关敏感性和对刺激波动的抗性至关重要。这些发现可能突出了为什么在胚胎发育和肿瘤发生的背景下let-7对于正常基因表达是必需的，这将有助于通过操纵Lin28/let-7轴来开发利用这种调节途径治疗人类疾病的新方法。
