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.

High gene dosage changes transcriptional regulation of genetic structures and contributes to diversity and heterogeneity

“…This observation suggests that LRCs could be more abundant in cells with high gene dosages or higher number of ploidy because they are more efficient in passing signals, which is consistent with our previous observation that in human, gene regulatory chains are shorter in human non-cancer cell line compared with cancer cell line [11,12].…”

“…Long linear regulatory chains (LRCs) is an interesting structure in genetic networks [11,12,22,23], in our previous publication, we showed, in gene regulatory networks, LRCs reduced the effect of the regulation from input signals by bringing down relative effectiveness (RE) and thus make long LRCs inefficient in passing information (Figure 3 A and B) [11,12]. An example of an inhibitory LRC, in which each gene is inhibited and only inhibited by its direct upstream gene via transcription factor, is shown in Figure 3A.…”

“…To investigate the effects of gene dosage variation at systems level, we decided to approach this issue by employing mathematical analysis of different genetic circuits that are found to recur in genetic networks across different organisms, i.e., self-inhibition, cross-repressors and inhibition chains [11][12][13]. In particular, we explored the changes in the quantitative dynamics of gene expression of the circuits when the gene dosage increased from low (≈ 1) to very high (≫ 1).…”

Balance of thrones: a network study on Game of Thrones

“…Although a network representation is a powerful way to describe the structure of a system of interacting entities, the actual dynamics of the system depends on many specificities that are abstracted away when a network is produced. Nonetheless, it is sometime possible to associate certain types of dynamics with particular network structures [17][18][19][20] . In the context of social interaction, the theory of structural balance has been used to formally explore how positive (e.g., friendship) and negative (e.g., hate) interactions can produce situations that are more or less balanced due to the psychological stress of the interacting agents.…”

Gene regulatory and signaling networks exhibit distinct topological distributions of motifs

“…Of particular interest, then, are certain ubiquitous interaction patterns (or subgraphs), which have been termed motifs [2,12]. The switch, the feed-forward motif and the feedback loop, shown in Figure 2, are examples of this class, and all of them have been shown to possess special dynamical properties regarding signal transduction and transmission [13][14][15][16].…”