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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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Related in: MedlinePlus

BQS in the GRN of dendritic cells.As discussed in the main text, various degrees of stability can be observed in the GRN of dendritic cells when they are in the process of activating a new transcriptional program. The GRN is very stable 0.5 hr after the new transcriptional program has been initiated (A–D), it is unstable after 1 hr (E–H), but partially stabilizes after 2 hr (I–L). The comparison of (D, H and L) indicates that a change in the balance between the number of inputs and outputs of a few TFs plays a strong role in controlling the stability of the GRN. To provide a better understanding of the dynamics, in (D, H and L), the TFs with the most unbalanced input/output are labelled. Looking at the labelled TFs it is possible to notice how they tend to move towards the centre of the plot in panel H and move back to the sides in (L).DOI:http://dx.doi.org/10.7554/eLife.02863.036
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fig9s1: BQS in the GRN of dendritic cells.As discussed in the main text, various degrees of stability can be observed in the GRN of dendritic cells when they are in the process of activating a new transcriptional program. The GRN is very stable 0.5 hr after the new transcriptional program has been initiated (A–D), it is unstable after 1 hr (E–H), but partially stabilizes after 2 hr (I–L). The comparison of (D, H and L) indicates that a change in the balance between the number of inputs and outputs of a few TFs plays a strong role in controlling the stability of the GRN. To provide a better understanding of the dynamics, in (D, H and L), the TFs with the most unbalanced input/output are labelled. Looking at the labelled TFs it is possible to notice how they tend to move towards the centre of the plot in panel H and move back to the sides in (L).DOI:http://dx.doi.org/10.7554/eLife.02863.036

Mentions: Since a full eukaryotic transcriptional response typically requires >1 hr, we expect the ‘0.5 hr’ network to be similar to the ‘0 hr’ one. Indeed, the ‘0.5 hr’ network still satisfies all the predictions of BQS and strongly resembles the ‘0 hr’ network (Figure 9A,B,G). In contrast, at 1 and 2 hr after the stimulus, a marked deviation from BQS is observed. A significant number of new long loops are created, peaking at 1 hr and declining slightly by 2 hr (Figure 9C,E). 22 long feedback loops remain at 2 hr, but interestingly all depend on the transcriptional interaction between RUNX1 and CEBPB. The probability of creating additional long feedback loops is noticeably larger at 1 and 2 hr than in the previous networks (Figure 9G). There is also a significant increase in the number of 4-node unbuffered motifs at 1 hr, though this does not persist in the ‘2 hr’ GRN. However, some components of BQS remain unchanged in the stimulus response. Incomplete feedback loops still remain preferentially short (Figure 9—figure supplement 1A,E,I), TF cross regulation remains essentially unchanged (Figure 9—figure supplement 1D,H,L) and the numbers of unbuffered 3-node motifs (Figure 9—figure supplement 1B,F,J) and unregulated TFs (Figure 9—figure supplement 1C,G,K) remain low. Taken together, these observations show that in response to a stimulus that changes the transcriptional profile, there is a modest and probably transient loss of BQS as the GRN moves into a new configuration.10.7554/eLife.02863.035Figure 9.BQS during a transcriptional program activation in dendritic cells.


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

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

BQS in the GRN of dendritic cells.As discussed in the main text, various degrees of stability can be observed in the GRN of dendritic cells when they are in the process of activating a new transcriptional program. The GRN is very stable 0.5 hr after the new transcriptional program has been initiated (A–D), it is unstable after 1 hr (E–H), but partially stabilizes after 2 hr (I–L). The comparison of (D, H and L) indicates that a change in the balance between the number of inputs and outputs of a few TFs plays a strong role in controlling the stability of the GRN. To provide a better understanding of the dynamics, in (D, H and L), the TFs with the most unbalanced input/output are labelled. Looking at the labelled TFs it is possible to notice how they tend to move towards the centre of the plot in panel H and move back to the sides in (L).DOI:http://dx.doi.org/10.7554/eLife.02863.036
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4151086&req=5

fig9s1: BQS in the GRN of dendritic cells.As discussed in the main text, various degrees of stability can be observed in the GRN of dendritic cells when they are in the process of activating a new transcriptional program. The GRN is very stable 0.5 hr after the new transcriptional program has been initiated (A–D), it is unstable after 1 hr (E–H), but partially stabilizes after 2 hr (I–L). The comparison of (D, H and L) indicates that a change in the balance between the number of inputs and outputs of a few TFs plays a strong role in controlling the stability of the GRN. To provide a better understanding of the dynamics, in (D, H and L), the TFs with the most unbalanced input/output are labelled. Looking at the labelled TFs it is possible to notice how they tend to move towards the centre of the plot in panel H and move back to the sides in (L).DOI:http://dx.doi.org/10.7554/eLife.02863.036
Mentions: Since a full eukaryotic transcriptional response typically requires >1 hr, we expect the ‘0.5 hr’ network to be similar to the ‘0 hr’ one. Indeed, the ‘0.5 hr’ network still satisfies all the predictions of BQS and strongly resembles the ‘0 hr’ network (Figure 9A,B,G). In contrast, at 1 and 2 hr after the stimulus, a marked deviation from BQS is observed. A significant number of new long loops are created, peaking at 1 hr and declining slightly by 2 hr (Figure 9C,E). 22 long feedback loops remain at 2 hr, but interestingly all depend on the transcriptional interaction between RUNX1 and CEBPB. The probability of creating additional long feedback loops is noticeably larger at 1 and 2 hr than in the previous networks (Figure 9G). There is also a significant increase in the number of 4-node unbuffered motifs at 1 hr, though this does not persist in the ‘2 hr’ GRN. However, some components of BQS remain unchanged in the stimulus response. Incomplete feedback loops still remain preferentially short (Figure 9—figure supplement 1A,E,I), TF cross regulation remains essentially unchanged (Figure 9—figure supplement 1D,H,L) and the numbers of unbuffered 3-node motifs (Figure 9—figure supplement 1B,F,J) and unregulated TFs (Figure 9—figure supplement 1C,G,K) remain low. Taken together, these observations show that in response to a stimulus that changes the transcriptional profile, there is a modest and probably transient loss of BQS as the GRN moves into a new configuration.10.7554/eLife.02863.035Figure 9.BQS during a transcriptional program activation in 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