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 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.

Chaos, Adaptation and Information are the Main Pillars of Carcinogenesis

“…The behavior (phenotype) of SSCs is controlled by coordinated activation and/or inhibition of thousands of genes. This coordination is achieved via a complex network of gene regulation that enables a cell to express the appropriate set of genes for a particular environment and/or phenotype [18]. The genome just needs to have enough instructions to recreate the required microenvironment so that the behavior can be sufficiently replicated within the required space to serve the required function.…”

“…Liu et al demonstrated that, potential chaotic motifs are seen in the expression of certain genes in the cancer cell line and they conclude that more complex and somewhat more disorganized chaotic motifs can be found in cancer [18]. Ghosh et al considered a mathematic model, describing the interactions of cancer cells with their microenvironment and they demonstrated chaotic behavior of cancer cell [39].…”