Universal attenuators and their interactions with feedback loops in gene regulatory networks

Abstract

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 analysing the preponderance of LRCs in the GRNs of E. 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.\n\nIn briefWe present a general principle that linear regulatory chains exponentially attenuate the range of expression in gene regulatory networks. The discovery of a universal interplay between linear regulatory chains and genetic feedback loops in microorganisms and a human cancer cell line is analysed and discussed.\n\nHighlightsWithin gene networks, linear regulatory chains act as exponentially strong attenuators of upstream variation\n\nBecause of their exponential behaviour, linear regulatory chains beyond a few genes provide no additional functionality and are rarely observed in gene networks across a range of different organisms\n\nNovel interactions between four-gene linear regulatory chains and feedback loops were discovered in E. coli, M. tuberculosis and human cancer cells, suggesting a universal mechanism of control.