Efficient Handling of Large Signalling-Regulatory Networks by Focusing on Their Core Control

  • Aurélien Naldi
  • Pedro T. Monteiro
  • Claudine Chaouiya
Part of the Lecture Notes in Computer Science book series (LNCS, volume 7605)


Considering the logical (Boolean or multi-valued) asynchronous framework, we delineate a reduction strategy for large signalling and regulatory networks. Consequently, focusing on the core network that drives the whole dynamics, we can check which attractors are reachable from given initial conditions, under fixed or varying environmental conditions.

More specifically, the dynamics of logical models are represented by (asynchronous) state transition graphs that grow exponentially with the number of model components. We introduce adequate reduction methods (preserving reachability of the attractors) and proceed with model-checking approaches.

Input nodes (that generally represent receptors) and output nodes (that constitute readouts of network behaviours) are each specifically processed to reduce the state space. The proposed approach is made available within GINsim, our software dedicated to the definition and analysis of logical models. The new GINsim functionalities consist in a proper reduction of output components, as well as the corresponding symbolic encoding of logical models for the NuSMV model checker. This encoding also includes a reduction over input components (transferring their values from states to transitions labels). Finally, we demonstrate the interest of the proposed methods through their application to a published large scale model of the signalling pathway involved in T cell activation.


Qualitative modelling Logical modelling Model checking Regulatory networks Signalling networks 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Bilke, S., Sjunnesson, F.: Stability of the Kauffman model. Phys. Rev. E 65(016129) (2001)Google Scholar
  2. 2.
    Cimatti, A., Clarke, E., Giunchiglia, E., Giunchiglia, F., Pistore, M., Roveri, M., Sebastiani, R., Tacchella, A.: NuSMV 2: An OpenSource Tool for Symbolic Model Checking. In: Brinksma, E., Larsen, K.G. (eds.) CAV 2002. LNCS, vol. 2404, pp. 359–364. Springer, Heidelberg (2002)CrossRefGoogle Scholar
  3. 3.
    Clarke, E.M., Emerson, E.A., Sistla, A.P.: Automatic verification of finite-state concurrent systems using temporal logic specifications. ACM Trans. Program. Lang. Syst. 8, 244–263 (1986)CrossRefzbMATHGoogle Scholar
  4. 4.
    de Jong, H.: Modeling and simulation of genetic regulatory systems: a literature review. J. Comput Biol. 1(9), 67–103 (2002)CrossRefGoogle Scholar
  5. 5.
    Fauré, A., Naldi, A., Chaouiya, C., Thieffry, D.: Dynamical analysis of a generic boolean model for the control of the mammalian cell cycle. Bioinformatics 22(14), 124–131 (2006)CrossRefGoogle Scholar
  6. 6.
    Lomuscio, A., Pecheur, C., Raimondi, F.: Automatic verification of knowledge and time with nusmv. In: Veloso, M.M. (ed.) Proc. 20th Intl. Joint Conf. on Artificial Intelligence (IJCAI 2007), pp. 1384–1389. Morgan Kaufmann Publishers Inc. (2007)Google Scholar
  7. 7.
    Müller-Olm, M., Schmidt, D., Steffen, B.: Model-Checking: A Tutorial Introduction. In: Cortesi, A., Filé, G. (eds.) SAS 1999. LNCS, vol. 1694, pp. 330–354. Springer, Heidelberg (1999)CrossRefGoogle Scholar
  8. 8.
    Monteiro, P.T., Chaouiya, C.: Efficient Verification for Logical Models of Regulatory Networks. In: Rocha, M.P., Luscombe, N., Fdez-Riverola, F., Rodríguez, J.M.C. (eds.) 6th International Conference on PACBB. AISC, vol. 154, pp. 259–267. Springer, Heidelberg (2012)CrossRefGoogle Scholar
  9. 9.
    Naldi, A., Berenguier, D., Fauré, A., Lopez, F., Thieffry, D., Chaouiya, C.: Logical modelling of regulatory networks with GINsim 2.3. Biosystems 97(2), 134–139 (2009)CrossRefGoogle Scholar
  10. 10.
    Naldi, A., Carneiro, J., Chaouiya, C., Thieffry, D.: Diversity and plasticity of th cell types predicted from regulatory network modelling. PLoS Comput. Biol. 6(9) (2010)Google Scholar
  11. 11.
    Naldi, A., Remy, E., Thieffry, D., Chaouiya, C.: Dynamically consistent reduction of logical regulatory graphs. Theor. Comput. Sci. 412, 2207–2218 (2011)MathSciNetCrossRefzbMATHGoogle Scholar
  12. 12.
    Naldi, A., Thieffry, D., Chaouiya, C.: Decision Diagrams for the Representation and Analysis of Logical Models of Genetic Networks. In: Calder, M., Gilmore, S. (eds.) CMSB 2007. LNCS (LNBI), vol. 4695, pp. 233–247. Springer, Heidelberg (2007)CrossRefGoogle Scholar
  13. 13.
    Pecheur, C., Raimondi, F.: Symbolic Model Checking of Logics with Actions. In: Edelkamp, S., Lomuscio, A. (eds.) MoChArt IV. LNCS (LNAI), vol. 4428, pp. 113–128. Springer, Heidelberg (2007)CrossRefGoogle Scholar
  14. 14.
    Remy, E., Ruet, P.: From minimal signed circuits to the dynamics of boolean regulatory networks. Bioinformatics 24(16), i220–i226 (2008)CrossRefGoogle Scholar
  15. 15.
    Saadatpour, A., Albert, I., Albert, R.: Attractor analysis of asynchronous boolean models of signal transduction networks. J. Theor. Biol. 266(4), 641–656 (2010)MathSciNetCrossRefGoogle Scholar
  16. 16.
    Saez-Rodriguez, J., Simeoni, L., Lindquist, J., Hemenway, R., Bommhardt, U., Arndt, B., Haus, U.-U., Weismantel, R., Gilles, E., Klamt, S., Schraven, B.: A logical model provides insights into T cell receptor signaling. PLoS Comput. Biol. 3(8), e163 (2007)Google Scholar
  17. 17.
    Saez-Rodriguez, J., Simeoni, L., Lindquist, J.A., Hemenway, R., Bommhardt, U., Arndt, B., Haus, U.-U., Weismantel, R., Gilles, E.D., Klamt, S., Schraven, B.: A logical model provides insights into T cell receptor signaling. PLoS Comput. Biol. 3(8), e163 (2007)Google Scholar
  18. 18.
    Schlitt, T., Brazma, A.: Current approaches to gene regulatory network modelling. BMC Bioinformatics 8(suppl. 6), S9 (2007)CrossRefGoogle Scholar
  19. 19.
    Thieffry, D.: Dynamical roles of biological regulatory circuits. Brief. Bioinform. 8(4), 220–225 (2007)CrossRefGoogle Scholar
  20. 20.
    Thomas, R.: Regulatory networks seen as asynchronous automata: A logical description. J. Theor. Biol. 153, 1–23 (1991)CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Aurélien Naldi
    • 1
  • Pedro T. Monteiro
    • 2
  • Claudine Chaouiya
    • 2
  1. 1.Center for Integrative Genomics, Fac. of Biology and MedicineUniv. of LausanneSwitzerland
  2. 2.IGC, Instituto Gulbenkian de CiênciaOeirasPortugal

Personalised recommendations