An effective network reduction approach to find the dynamical repertoire of discrete dynamic networks.

Discrete dynamic models are a powerful tool for the understanding and modeling of large biological networks. Although a lot of progress has been made in developing analysis tools for these models, there is still a need to find approaches that can directly relate the network structure to its dynamics. Of special interest is identifying the stable patterns of activity, i.e., the attractors of the system. This is a problem for large networks, because the state space of the system increases exponentially with network size. In this work, we present a novel network reduction approach that is based on finding network motifs that stabilize in a fixed state. Notably, we use a topological criterion to identify these motifs. Specifically, we find certain types of strongly connected components in a suitably expanded representation of the network. To test our method, we apply it to a dynamic network model for a type of cytotoxic T cell cancer and to an ensemble of random Boolean networks of size up to 200. Our results show that our method goes beyond reducing the network and in most cases can actually predict the dynamical repertoire of the nodes (fixed states or oscillations) in the attractors of the system.

[1]  H. Othmer,et al.  The topology of the regulatory interactions predicts the expression pattern of the segment polarity genes in Drosophila melanogaster. , 2003, Journal of theoretical biology.

[2]  Rui-Sheng Wang,et al.  Effects of community structure on the dynamics of random threshold networks. , 2013, Physical review. E, Statistical, nonlinear, and soft matter physics.

[3]  J. Gouzé Positive and Negative Circuits in Dynamical Systems , 1998 .

[4]  D. Thieffry,et al.  Dynamical behaviour of biological regulatory networks—I. Biological role of feedback loops and practical use of the concept of the loop-characteristic state , 1995 .

[5]  Florian Greil,et al.  Dynamics of critical Kauffman networks under asynchronous stochastic update. , 2005, Physical review letters.

[6]  Alan Veliz-Cuba Reduction of Boolean network models. , 2011, Journal of theoretical biology.

[7]  Maximino Aldana Dynamics of Boolean Networks with Scale-Free Topology , 2002 .

[8]  Assieh Saadatpour,et al.  A Reduction Method for Boolean Network Models Proven to Conserve Attractors , 2013, SIAM J. Appl. Dyn. Syst..

[9]  Réka Albert,et al.  But No Kinetic Details Needed , 2003 .

[10]  S. Bilke,et al.  Stability of the Kauffman model. , 2002, Physical review. E, Statistical, nonlinear, and soft matter physics.

[11]  Thomas Mestl,et al.  FEEDBACK LOOPS, STABILITY AND MULTISTATIONARITY IN DYNAMICAL SYSTEMS , 1995 .

[12]  René Thomas On the Relation Between the Logical Structure of Systems and Their Ability to Generate Multiple Steady States or Sustained Oscillations , 1981 .

[13]  Madalena Chaves,et al.  Robustness and fragility of Boolean models for genetic regulatory networks. , 2005, Journal of theoretical biology.

[14]  J. Monod,et al.  Genetic regulatory mechanisms in the synthesis of proteins. , 1961, Journal of Molecular Biology.

[15]  C. Soulé Graphic Requirements for Multistationarity , 2004, Complexus.

[16]  Donald B. Johnson,et al.  Finding All the Elementary Circuits of a Directed Graph , 1975, SIAM J. Comput..

[17]  Xin Liu,et al.  Dynamical and Structural Analysis of a T Cell Survival Network Identifies Novel Candidate Therapeutic Targets for Large Granular Lymphocyte Leukemia , 2011, PLoS Comput. Biol..

[18]  R. Albert,et al.  Discrete dynamic modeling of cellular signaling networks. , 2009, Methods in enzymology.

[19]  Dominik M. Wittmann,et al.  Biologically meaningful update rules increase the critical connectivity of generalized Kauffman networks. , 2010, Journal of theoretical biology.

[20]  Elisabeth Remy,et al.  On Differentiation and Homeostatic Behaviours of Boolean Dynamical Systems , 2006, Trans. Comp. Sys. Biology.

[21]  Réka Albert,et al.  Elementary signaling modes predict the essentiality of signal transduction network components , 2011, BMC Systems Biology.

[22]  Denis Thieffry,et al.  Graphic requirements for multistability and attractive cycles in a Boolean dynamical framework , 2008, Adv. Appl. Math..

[23]  Barbara Drossel,et al.  Scaling in a general class of critical random Boolean networks. , 2006, Physical review. E, Statistical, nonlinear, and soft matter physics.

[24]  C. Espinosa-Soto,et al.  A Gene Regulatory Network Model for Cell-Fate Determination during Arabidopsis thaliana Flower Development That Is Robust and Recovers Experimental Gene Expression Profilesw⃞ , 2004, The Plant Cell Online.

[25]  M Chaves,et al.  Methods of robustness analysis for Boolean models of gene control networks. , 2006, Systems biology.

[26]  Steffen Klamt,et al.  Structural and functional analysis of cellular networks with CellNetAnalyzer , 2007, BMC Systems Biology.

[27]  Katherine C. Chen,et al.  Sniffers, buzzers, toggles and blinkers: dynamics of regulatory and signaling pathways in the cell. , 2003, Current opinion in cell biology.

[28]  L. Glass Classification of biological networks by their qualitative dynamics. , 1975, Journal of theoretical biology.

[29]  A. Mogilner,et al.  Quantitative modeling in cell biology: what is it good for? , 2006, Developmental cell.

[30]  Volkan Sevim,et al.  Reliability of Transcriptional Cycles and the Yeast Cell-Cycle Oscillator , 2010, PLoS Comput. Biol..

[31]  Eric Goles Ch.,et al.  On limit cycles of monotone functions with symmetric connection graph , 2004, Theor. Comput. Sci..

[32]  Kathy Chen,et al.  Network dynamics and cell physiology , 2001, Nature Reviews Molecular Cell Biology.

[33]  Elisabeth Remy,et al.  From minimal signed circuits to the dynamics of Boolean regulatory networks , 2008, ECCB.

[34]  Ranran Zhang,et al.  Molecular profiling of LGL leukemia reveals role of sphingolipid signaling in survival of cytotoxic lymphocytes. , 2008, Blood.

[35]  Aprile Ja,et al.  Anti-CD3 monoclonal antibody-mediated cytotoxicity occurs through an interleukin-2-independent pathway in CD3+ large granular lymphocytes. , 1990 .

[36]  S. Kauffman Metabolic stability and epigenesis in randomly constructed genetic nets. , 1969, Journal of theoretical biology.

[37]  Ilya Shmulevich,et al.  Eukaryotic cells are dynamically ordered or critical but not chaotic. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[38]  Aurélien Naldi,et al.  Dynamically consistent reduction of logical regulatory graphs , 2011, Theor. Comput. Sci..

[39]  I. Albert,et al.  Attractor analysis of asynchronous Boolean models of signal transduction networks. , 2010, Journal of theoretical biology.

[40]  M. Aldana Boolean dynamics of networks with scale-free topology , 2003 .

[41]  Irina Kusmartseva,et al.  Constitutive production of proinflammatory cytokines RANTES, MIP-1beta and IL-18 characterizes LGL leukemia. , 2005, International journal of oncology.

[42]  Joshua E. S. Socolar,et al.  Global control of cell-cycle transcription by coupled CDK and network oscillators , 2008, Nature.

[43]  F. Ruscetti,et al.  Anti-CD3 monoclonal antibody-mediated cytotoxicity occurs through an interleukin-2-independent pathway in CD3+ large granular lymphocytes. , 1990, Blood.

[44]  Stefan Bornholdt,et al.  Less Is More in Modeling Large Genetic Networks , 2005, Science.

[45]  Gérard Y. Vichniac,et al.  Boolean derivatives on cellular automata , 1991 .

[46]  Steffen Klamt,et al.  A Logical Model Provides Insights into T Cell Receptor Signaling , 2007, PLoS Comput. Biol..

[47]  Andrew Wuensche,et al.  A model of transcriptional regulatory networks based on biases in the observed regulation rules , 2002, Complex..

[48]  Jorge G. T. Zañudo,et al.  Boolean Threshold Networks: Virtues and Limitations for Biological Modeling , 2010, 1011.3848.

[49]  R. Thomas,et al.  Boolean formalization of genetic control circuits. , 1973, Journal of theoretical biology.

[50]  René Thomas,et al.  Logical identification of all steady states: The concept of feedback loop characteristic states , 1993 .

[51]  El Houssine Snoussi Necessary Conditions for Multistationarity and Stable Periodicity , 1998 .

[52]  L. Hood,et al.  Gene expression dynamics in the macrophage exhibit criticality , 2008, Proceedings of the National Academy of Sciences.

[53]  L. Kadanoff,et al.  Boolean Dynamics with Random Couplings , 2002, nlin/0204062.

[54]  Heike Siebert,et al.  Deriving Behavior of Boolean Bioregulatory Networks from Subnetwork Dynamics , 2009, Math. Comput. Sci..

[55]  A. Barabasi,et al.  Network biology: understanding the cell's functional organization , 2004, Nature Reviews Genetics.

[56]  R. Albert,et al.  Network model of survival signaling in large granular lymphocyte leukemia , 2008, Proceedings of the National Academy of Sciences.

[57]  S A Kauffman,et al.  Scaling in ordered and critical random boolean networks. , 2002, Physical review letters.

[58]  D. Lauffenburger,et al.  Physicochemical modelling of cell signalling pathways , 2006, Nature Cell Biology.

[59]  L. Glass,et al.  The logical analysis of continuous, non-linear biochemical control networks. , 1973, Journal of theoretical biology.

[60]  A. Mogilner,et al.  Cell Polarity: Quantitative Modeling as a Tool in Cell Biology , 2012, Science.