Liu Dianbo, Albergante Luca, Newman Timothy J
School of Life sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA.
Nucleic Acids Res. 2017 Jul 7;45(12):7078-7093. doi: 10.1093/nar/gkx485.
Using a combination of mathematical modelling, statistical simulation and large-scale data analysis we study the properties of linear regulatory chains (LRCs) within gene regulatory networks (GRNs). Our modelling indicates that downstream genes embedded within LRCs are highly insulated from the variation in expression of upstream genes, and thus LRCs act as attenuators. This observation implies a progressively weaker functionality of LRCs as their length increases. When analyzing the preponderance of LRCs in the GRNs of Escherichia coli K12 and several other organisms, we find that very long LRCs are essentially absent. In both E. coli and M. tuberculosis we find that four-gene LRCs are intimately linked to identical feedback loops that are involved in potentially chaotic stress response, indicating that the dynamics of these potentially destabilising motifs are strongly restrained under homeostatic conditions. The same relationship is observed in a human cancer cell line (K562), and we postulate that four-gene LRCs act as 'universal attenuators'. These findings suggest a role for long LRCs in dampening variation in gene expression, thereby protecting cell identity, and in controlling dramatic shifts in cell-wide gene expression through inhibiting chaos-generating motifs.
通过结合数学建模、统计模拟和大规模数据分析，我们研究了基因调控网络（GRN）中的线性调控链（LRC）的特性。我们的建模表明，嵌入在LRC中的下游基因与上游基因表达的变化高度隔离，因此LRC起到衰减器的作用。这一观察结果意味着LRC的功能会随着其长度的增加而逐渐减弱。在分析大肠杆菌K12和其他几种生物的GRN中LRC的优势时，我们发现基本上不存在非常长的LRC。在大肠杆菌和结核分枝杆菌中，我们都发现四基因LRC与参与潜在混沌应激反应的相同反馈环密切相关，这表明在稳态条件下，这些潜在不稳定基序的动态受到强烈抑制。在人类癌细胞系（K562）中也观察到了相同的关系，我们推测四基因LRC充当“通用衰减器”。这些发现表明长LRC在抑制基因表达变化、从而保护细胞特性以及通过抑制产生混沌的基序来控制全细胞基因表达的剧烈变化方面发挥作用。
