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Buffered Qualitative Stability explains the robustness and evolvability of transcriptional networks.

Albergante L, Blow JJ, Newman TJ - Elife (2014)

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.

View Article: PubMed Central - PubMed

Affiliation: College of Life Sciences, University of Dundee, Dundee, United Kingdom l.albergante@dundee.ac.uk.

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Long feedback loops in the GRN of homeostatic dendritic cells.Three long feedback loops can be found in the GRN of homeostatic dendritic cells (A–C). However, all of them depend critically on the transcriptional interaction between Sfpi1 and E2f1. The interaction between Sfpi1 and E2f1 is highlighted in red for clarity. Note that such an interaction is the only one that is fundamental for the formation of all the long feedback loops.DOI:http://dx.doi.org/10.7554/eLife.02863.034
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fig8s1: Long feedback loops in the GRN of homeostatic dendritic cells.Three long feedback loops can be found in the GRN of homeostatic dendritic cells (A–C). However, all of them depend critically on the transcriptional interaction between Sfpi1 and E2f1. The interaction between Sfpi1 and E2f1 is highlighted in red for clarity. Note that such an interaction is the only one that is fundamental for the formation of all the long feedback loops.DOI:http://dx.doi.org/10.7554/eLife.02863.034

Mentions: The ‘0 hr’ GRN was obtained under conditions comparable with the organisms discussed previously. Figure 8 shows that all the predictions of BQS are met at this time. As indicated by Figure 8A, the GRN has a very limited number of long feedback loops (only three with three or more genes), in striking contrast with the hundreds observed in randomly generated networks of the same link density. Interestingly, all of the long feedback loops depend on the transcriptional interaction between SFPI1 and E2F1 (Figure 8—figure supplement 1A–C). Notably E2F1 plays a crucial role in the cell cycle and is only transiently activated at commitment to cell division at the end of G1. Therefore, all of the long feedback loops detected are likely to be transient. Similarly, the number of incomplete feedback loops is very small, and much lower than would be expected in random networks (Figure 8B). Motif analysis is also consistent with BQS: there is a much higher proportion of unregulated transcription factors than would be expected by chance (Figure 8E), and the proportion of stable 3- and 4-node motifs is heavily biased towards the buffered stable forms that enhance BQS (Figure 8C,D). Additionally, the mode of cross regulation—with transcription factors tending to be either highly regulating or highly regulated (Figure 8F)—also follows the distribution predicted by BQS. Finally, the probability of creating additional long feedback loops in the network by randomly inserting a new regulatory connection is only 0.18, much lower than the value of 0.74 expected in a comparable random network.10.7554/eLife.02863.033Figure 8.BQS in homeostatic murine dendritic cells.


Buffered Qualitative Stability explains the robustness and evolvability of transcriptional networks.

Albergante L, Blow JJ, Newman TJ - Elife (2014)

Long feedback loops in the GRN of homeostatic dendritic cells.Three long feedback loops can be found in the GRN of homeostatic dendritic cells (A–C). However, all of them depend critically on the transcriptional interaction between Sfpi1 and E2f1. The interaction between Sfpi1 and E2f1 is highlighted in red for clarity. Note that such an interaction is the only one that is fundamental for the formation of all the long feedback loops.DOI:http://dx.doi.org/10.7554/eLife.02863.034
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4151086&req=5

fig8s1: Long feedback loops in the GRN of homeostatic dendritic cells.Three long feedback loops can be found in the GRN of homeostatic dendritic cells (A–C). However, all of them depend critically on the transcriptional interaction between Sfpi1 and E2f1. The interaction between Sfpi1 and E2f1 is highlighted in red for clarity. Note that such an interaction is the only one that is fundamental for the formation of all the long feedback loops.DOI:http://dx.doi.org/10.7554/eLife.02863.034
Mentions: The ‘0 hr’ GRN was obtained under conditions comparable with the organisms discussed previously. Figure 8 shows that all the predictions of BQS are met at this time. As indicated by Figure 8A, the GRN has a very limited number of long feedback loops (only three with three or more genes), in striking contrast with the hundreds observed in randomly generated networks of the same link density. Interestingly, all of the long feedback loops depend on the transcriptional interaction between SFPI1 and E2F1 (Figure 8—figure supplement 1A–C). Notably E2F1 plays a crucial role in the cell cycle and is only transiently activated at commitment to cell division at the end of G1. Therefore, all of the long feedback loops detected are likely to be transient. Similarly, the number of incomplete feedback loops is very small, and much lower than would be expected in random networks (Figure 8B). Motif analysis is also consistent with BQS: there is a much higher proportion of unregulated transcription factors than would be expected by chance (Figure 8E), and the proportion of stable 3- and 4-node motifs is heavily biased towards the buffered stable forms that enhance BQS (Figure 8C,D). Additionally, the mode of cross regulation—with transcription factors tending to be either highly regulating or highly regulated (Figure 8F)—also follows the distribution predicted by BQS. Finally, the probability of creating additional long feedback loops in the network by randomly inserting a new regulatory connection is only 0.18, much lower than the value of 0.74 expected in a comparable random network.10.7554/eLife.02863.033Figure 8.BQS in homeostatic murine dendritic cells.

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.

View Article: PubMed Central - PubMed

Affiliation: College of Life Sciences, University of Dundee, Dundee, United Kingdom l.albergante@dundee.ac.uk.

Show MeSH
Related in: MedlinePlus