eLife, 2014

Pizza Club20 April 2016

Gaia Zaffaroni

Some terminology• GRN: gene regulatory network• A network is composed of:• Nodes, represent genes• Edges, represent interactions, e.g. protein-protein physical

interaction, co-expression, transcriptional regulation, …

• Topology: the structure of the network• Robustness: is a complex property of the system that

makes it able to tolerate a wide variety of perturbations (any change in the conditions) maintaining its function

Motifs

Tran, N. H. et al. Counting motifs in the human interactome. Nat. Commun. 4:2241 doi: 10.1038/ncomms3241 (2013).

Introduction• Interaction networks are a fundamental feature of biological

systems • Biological networks are stable: they can recover their

equilibrium state after perturbation• Selective pressure causes them to have specific topologies• Transcriptional networks:

• Nodes=genes and transcription factors• Edges=transcriptional regulation• Assumption: gene expression level corresponds to protein activity

level• these networks cannot capture post-transcriptional and

translational regulations

Real networks• Collection of curated transcriptional networks• Examples: E.coli, M.tuberculosis, P.aeruginosa,

S.cerevisiae, mouse and human

Hypothesis• To be stable, the network should not depend on the

change of any of the individual quantitative parameters• protein concentration, • affinity for a DNA sequence, • promoter availability, • rate of transcription

• It should also be stable to the addition of new links• The robustness then should depend on qualitative

features of the network

Qualitative Stability • The topology is stable even if the edge strength

changes• Mathematical concept:• Long feedback loops are negative for stability• They are in general associated with oscillations, but in a

real system they can cause chaotic behavior

Presence of feedback loops

Presence of incomplete feedback loops

TF regulation

Motifs

Illegal feedback loops

E. coli There are 7 2-node feedback loops:4 are into potentially instable motifs3 can act as switches

These genes are related with drug resistance and/or acid resistance

Similar configuration that can display chaotic behavior

Cancer cellsK562 (Leukemia cell line)GM12878 (non-cancer cell line)

Dynamic networksMurine dentritic cells after stimulation with pathogens

Dynamic networks

Conclusions• BQS allows to do new predictions based on the

robustness “criteria”• It provides theoretical justification for observed

network features• It helps in explaining the overall structure of GRNs

at different scales