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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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Cross regulation and second-order cross regulation in cancer.TF cross regulation (A) and second-order cross regulation (B) display in cancer similar overall trend when compared to E. coli, yeast and the non-cancer cell line (Figure 4, Figure 4—figure supplement 3). However, a slightly less stringent distribution can be observed, compatible with a diminished stability.DOI:http://dx.doi.org/10.7554/eLife.02863.031
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fig7s2: Cross regulation and second-order cross regulation in cancer.TF cross regulation (A) and second-order cross regulation (B) display in cancer similar overall trend when compared to E. coli, yeast and the non-cancer cell line (Figure 4, Figure 4—figure supplement 3). However, a slightly less stringent distribution can be observed, compatible with a diminished stability.DOI:http://dx.doi.org/10.7554/eLife.02863.031

Mentions: Cancer cells have a dysregulated behaviour, breaking the ‘social contract’ necessary for maintenance of a healthy multicellular organism. Even within an individual tumour a wide range of cellular phenotypes is often observed (Marusyk et al., 2012). To some degree, this is likely to be a consequence of the genotypic heterogeneity of tumours. However, cancer cells also appear to be phenotypically less stable than normal cells (Brock et al., 2009; Gupta et al., 2011). Might this phenotypic instability result from a breakdown of BQS in cancer cells? There is currently only a single cancer cell line, the human leukaemia cell line K562, for which a high quality system-wide GRN has been derived (Gerstein et al., 2012). We therefore investigated the topological differences between the GRNs of K562 and the human non-cancer cell line GM12878. Figure 7 and Figure 7—figure supplement 1 show that the feedback loop distribution in the GRN of the leukaemia cell line is strikingly different from that of the non-cancer cell line. In K562, significantly more moderately long feedback loops of 4–8 genes are present (Figure 7A,B), and the number of loops formed by 3–5 genes is comparable to the number expected in a random network (Figure 7A). The number of incomplete feedback loops is also significantly larger in K562 (Figure 7C,D). In addition, poorly buffered motifs are abundant (Figure 7E,F) and the TFs cross regulation is less extreme (Figure 7—figure supplement 2A,B).10.7554/eLife.02863.029Figure 7.Broken BQS in a human cancer cell line.


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

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

Cross regulation and second-order cross regulation in cancer.TF cross regulation (A) and second-order cross regulation (B) display in cancer similar overall trend when compared to E. coli, yeast and the non-cancer cell line (Figure 4, Figure 4—figure supplement 3). However, a slightly less stringent distribution can be observed, compatible with a diminished stability.DOI:http://dx.doi.org/10.7554/eLife.02863.031
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig7s2: Cross regulation and second-order cross regulation in cancer.TF cross regulation (A) and second-order cross regulation (B) display in cancer similar overall trend when compared to E. coli, yeast and the non-cancer cell line (Figure 4, Figure 4—figure supplement 3). However, a slightly less stringent distribution can be observed, compatible with a diminished stability.DOI:http://dx.doi.org/10.7554/eLife.02863.031
Mentions: Cancer cells have a dysregulated behaviour, breaking the ‘social contract’ necessary for maintenance of a healthy multicellular organism. Even within an individual tumour a wide range of cellular phenotypes is often observed (Marusyk et al., 2012). To some degree, this is likely to be a consequence of the genotypic heterogeneity of tumours. However, cancer cells also appear to be phenotypically less stable than normal cells (Brock et al., 2009; Gupta et al., 2011). Might this phenotypic instability result from a breakdown of BQS in cancer cells? There is currently only a single cancer cell line, the human leukaemia cell line K562, for which a high quality system-wide GRN has been derived (Gerstein et al., 2012). We therefore investigated the topological differences between the GRNs of K562 and the human non-cancer cell line GM12878. Figure 7 and Figure 7—figure supplement 1 show that the feedback loop distribution in the GRN of the leukaemia cell line is strikingly different from that of the non-cancer cell line. In K562, significantly more moderately long feedback loops of 4–8 genes are present (Figure 7A,B), and the number of loops formed by 3–5 genes is comparable to the number expected in a random network (Figure 7A). The number of incomplete feedback loops is also significantly larger in K562 (Figure 7C,D). In addition, poorly buffered motifs are abundant (Figure 7E,F) and the TFs cross regulation is less extreme (Figure 7—figure supplement 2A,B).10.7554/eLife.02863.029Figure 7.Broken BQS in a human cancer cell line.

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