Buffered Qualitative Stability explains the robustness and evolvability of transcriptional networks.
Bottom Line: The gene regulatory network (GRN) is the central decision-making module of the cell.BQS explains many of the small- and large-scale properties of GRNs, provides conditions for evolvable robustness, and highlights general features of transcriptional response.BQS is severely compromised in a human cancer cell line, suggesting that loss of BQS might underlie the phenotypic plasticity of cancer cells, and highlighting a possible sequence of GRN alterations concomitant with cancer initiation.
Affiliation: College of Life Sciences, University of Dundee, Dundee, United Kingdom email@example.com.Show MeSH
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Mentions: Certain features of GRNs, such as rare, long incomplete feedback loops, make them more susceptible to the formation of long feedback loops when new regulatory connections are added (Figure 7—figure supplement 3A–G). Therefore, we investigated how many of the long feedback loops observed in K562 cancer cells could have originated from these relatively unbuffered network structures in non-cancerous GM12878 cells. We find that the three genes that contribute the most to the formation of long feedback loops in the cancer cell line (EGR1, FOSL1, and JUNB) are all involved in the formation of the longest incomplete feedback loops observed in the non-cancer cell line (Figure 7G). As highlighted earlier (Supplementary file 1), single insertions of a new connection into the non-cancer human cell line can create 48 different long feedback loops. Of these 48 potentially destabilising interactions of the non-cancer cell line, three are actually observed in the cancer cell line, namely JUNB-BCLAF1, BATF-EBF1, and JUNB-EBF1. The likelihood of these potentially destabilising interactions occurring in the cancer cell line is 3/48 = 0.063. In comparison, there are a total of 4363 additional links that could be made between the TFs of the non-cancer cell line. Of these potential links, 56 are observed in the cancer cell line. Hence, the links observed represent 56/4363 (0.013) of all the possible ones. Therefore, the destabilizing interactions are five times more abundant than would be expected by chance (0.063 vs 0.013), consistent with the idea that destabilizing interactions were positively selected for during the microevolution process underlying cancer progression. This suggests that, despite the diverse biological histories of these two cell lines (the networks of GM12878 and K562 share only four common links between TFs), the progression of K562 into a cancerous state has involved changes to regions of the GRN in the progenitor normal cells that displayed weaker BQS. Such genetic factors are therefore likely to play a pivotal role in the process of cancer progression in other cell types.
Affiliation: College of Life Sciences, University of Dundee, Dundee, United Kingdom firstname.lastname@example.org.