Qualitative modelling of post-transcriptional effects in the EWS/FLI1 signalling network

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Nicholas Booker
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1 Qualitative modelling of post-transcriptional effects in the EWS/FLI1 signalling network Carito Guziolowski Project Symbiose - IRISA - INRIA May 2008

2 How to analyse EWS/FLI1 network? 1 Construct a influence network from interaction knowledge 2 Integrate qualitative experimental data: +, if mrna is correlated with EWS/FLI1,, if mrna is anti-correlated with EWS/FLI1 3 Test the consistency of the whole with Bioquali 4 Make {+, } predictions on the network products Compare predictions with experimental results Propose experiments if interesting

3 Qualitative modelling object: Influence network Signed and oriented graph Nodes: mrna active protein protein complex? protein family/group? Edges: influences over production A > C : Increase of product A influences production of C Edges are labeled as: + : activation (trans or post-trans) : inhibition (trans or post-trans) Bindings, indirect influences, phosphorylation, sequestration, release...?

4 Qualitative modelling object: Influence network Signed and oriented graph Nodes: mrna active protein protein complex? protein family/group? Edges: influences over production A > C : Increase of product A influences production of C Edges are labeled as: + : activation (trans or post-trans) : inhibition (trans or post-trans) Bindings, indirect influences, phosphorylation, sequestration, release...?

5 Qualitative modelling object: Influence network Signed and oriented graph Nodes: mrna active protein protein complex? protein family/group? Edges: influences over production A > C : Increase of product A influences production of C Edges are labeled as: + : activation (trans or post-trans) : inhibition (trans or post-trans) Bindings, indirect influences, phosphorylation, sequestration, release...?

6 mrna Influence network: Nodes (1) active protein consistent cases for simple qualitative rule A B C ? A B C ? A B C + +?? + +

7 Influence network: Nodes (2) protein complex: RBL1 E2F5 RBL1:E2F5 cc S protein families/groups (expanded) Collapsed: Expanded:

8 Influence network: Nodes (3) Main interest: Predict +, state of any node in the network (mrna, active protein, protein complex) from an initial set of mrna correlations

9 Influence network: Edges (1) Modelling phosphorylation: RB1 example active protein RB1 = hypophosphorylated RB1 Old model: New one:

10 Influence network: Edges (2) Modelling Competitions: RB1, (E2F.) example RB1 does not directly inhibit (E2F.) Both proteins and the cell cycle S may be active (+) at the same moment Old modelisation: New one:

11 Influence network: Edges (3) Model: Modelling Competitions: active RB1 wins active (E2F.) in the cell cycle S control Known behaviour: (E2F.) RB1 E2F:RB1 cc S

12 Influence network: Edges (4) What we need is to add a new complex qualitative rule: f(e2f, RB1) > cell cycle S Hopefully, Bioquali now has evolve and is able to parse and interpret new rules (coding sign tables) for certain products with known (literature) qualitative behaviour

13 Influence network: Edges (4) What we need is to add a new complex qualitative rule: f(e2f, RB1) > cell cycle S Hopefully, Bioquali now has evolve and is able to parse and interpret new rules (coding sign tables) for certain products with known (literature) qualitative behaviour

14 Summary We modified the EWS/FLI1 influence network to be used by Bioquali by reading the literature (thanks Sylvain) Nodes: mrna and active protein form of a gene were included Protein complex rule was added Protein families and groups were splited Some proteins were deleted from the model (PDGFRL) Edges: Phosphorylation influences added 2 inhibitor-activator competition models were studied and their rules were added Bioquali now allows to add more restrictive (logical) rules in the interactions (thanks Michel)

15 Future work... Run Bioquali on the new regulatory model Study predictions or inconsistencies Can we change the Bioquali prediction in a component of the network, by blocking a pathway?

16 Thank you!

Adding missing post-transcriptional regulations to a regulatory network

Adding missing post-transcriptional regulations to a regulatory network Carito Guziolowski, Sylvain Blachon, Anne Siegel Project Symbiose - IRISA-INRIA - Rennes Journée satellite JOBIM 2008 Approach Objective: