title: Bistable switch in let-7 miRNA biogenesis pathway involving Lin28.
abstract: 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.
authors.affiliation: College of Veterinary Medicine, Sichuan Agricultural University, Ya'an 625014, Sichuan, China. dfeijtgf@gmail.com.
authors.forename: Fei
authors.initials: F
authors.lastname: Shi
authors.affiliation: Department of Statistics, Seoul National University, Seoul 151-742, Korea. wbaoyu@ejnu.net.
authors.forename: Wenbao
authors.initials: W
authors.lastname: Yu
authors.affiliation: School of Medical Engineering, Hefei University of Technology, Hefei 230009, Anhui, China. fishery18@163.com.
authors.forename: Xia
authors.initials: X
authors.lastname: Wang
mesh_terms: D003198:Computer Simulation; D015870:Gene Expression / Q000235:genetics*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D008954:Models, Biological; D016601:RNA-Binding Proteins / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D012984:Software
chemical_list: C000715187:Lin28A protein, human; D035683:MicroRNAs; D016601:RNA-Binding Proteins; C487931:mirnlet7 microRNA, human