Controlling Large Boolean Networks with Temporary and Permanent Perturbations

A salient objective of studying gene regulatory networks (GRNs) is to identify potential target genes whose perturbations would lead to effective treatment of diseases. In this paper, we develop two control methods for GRNs in the context of asynchronous Boolean networks. Our methods compute a minimal subset of nodes of a given Boolean network, such that temporary or permanent perturbations of these nodes drive the network from an initial state to a target steady state. The main advantages of our methods include: (1) temporary and permanent perturbations can be feasibly conducted with techniques for genetic modifications in biological experiments; and (2) the minimality of the identified control sets can reduce the cost of experiments to a great extent. We apply our methods to several real-life biological networks in silico to show their efficiency in terms of computation time and their efficacy with respect to the number of nodes to be perturbed.

[1]  Albert-László Barabási,et al.  Controllability of complex networks , 2011, Nature.

[2]  Melanie Boerries,et al.  Boolean approach to signalling pathway modelling in HGF-induced keratinocyte migration , 2012, Bioinform..

[3]  Edward R. Dougherty,et al.  Probabilistic Boolean Networks - The Modeling and Control of Gene Regulatory Networks , 2010 .

[4]  Simon C. Potter,et al.  A Genome-Wide Association Search for Type 2 Diabetes Genes in African Americans , 2012, PLoS ONE.

[5]  Jongrae Kim,et al.  Aggregation Algorithm Towards Large-Scale Boolean Network Analysis , 2013, IEEE Transactions on Automatic Control.

[6]  Jun Pang,et al.  An Efficient Approach Towards the Source-Target Control of Boolean Networks , 2020, IEEE/ACM Transactions on Computational Biology and Bioinformatics.

[7]  Y. Vassetzky,et al.  A Comparison of Techniques to Evaluate the Effectiveness of Genome Editing. , 2017, Trends in biotechnology.

[8]  Gang Yang,et al.  Structure-based control of complex networks with nonlinear dynamics , 2016, Proceedings of the National Academy of Sciences.

[9]  Yan Lin,et al.  DEG 5.0, a database of essential genes in both prokaryotes and eukaryotes , 2008, Nucleic Acids Res..

[10]  Jun Pang,et al.  A Decomposition-based Approach towards the Control of Boolean Networks , 2018, BCB.

[11]  Tomáš Helikar,et al.  Design, Assessment, and in vivo Evaluation of a Computational Model Illustrating the Role of CAV1 in CD4+ T-lymphocytes , 2014, Front. Immunol..

[12]  S. Kauffman Homeostasis and Differentiation in Random Genetic Control Networks , 1969, Nature.

[13]  Jie Han,et al.  Asynchronous Stochastic Boolean Networks as Gene Network Models , 2014, J. Comput. Biol..

[14]  A. Sol,et al.  Concise Review: A Population Shift View of Cellular Reprogramming , 2014, Stem cells.

[15]  Kwang-Hyun Cho,et al.  Discovery of a kernel for controlling biomolecular regulatory networks , 2013, Scientific Reports.

[16]  Jun Pang,et al.  Sequential Reprogramming of Boolean Networks Made Practical , 2019, CMSB.

[17]  Jun Pang,et al.  Recent development and biomedical applications of probabilistic Boolean networks , 2013, Cell Communication and Signaling.

[18]  Emmanuel Barillot,et al.  Mathematical Modelling of Molecular Pathways Enabling Tumour Cell Invasion and Migration , 2015, PLoS Comput. Biol..

[19]  Denis Thieffry,et al.  Logical modeling of lymphoid and myeloid cell specification and transdifferentiation , 2017, Proceedings of the National Academy of Sciences.

[20]  Albert-László Barabási,et al.  Target control of complex networks , 2014, Nature Communications.

[21]  Wen-Xu Wang,et al.  A geometrical approach to control and controllability of nonlinear dynamical networks , 2016, Nature Communications.

[22]  Deepak Srivastava,et al.  In Vivo Cellular Reprogramming: The Next Generation , 2016, Cell.

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

[24]  B. Fiedler,et al.  Dynamics and control at feedback vertex sets. II: a faithful monitor to determine the diversity of molecular activities in regulatory networks. , 2013, Journal of theoretical biology.

[25]  Holger Fröhlich,et al.  Modeling ERBB receptor-regulated G1/S transition to find novel targets for de novo trastuzumab resistance , 2009, BMC Systems Biology.

[26]  Denis Thieffry,et al.  Integrative Modelling of the Influence of MAPK Network on Cancer Cell Fate Decision , 2013, PLoS Comput. Biol..

[27]  S. Yamanaka,et al.  Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors , 2006, Cell.

[28]  Jason A. Papin,et al.  Reconstruction of cellular signalling networks and analysis of their properties , 2005, Nature Reviews Molecular Cell Biology.

[29]  T. Enver,et al.  Forcing cells to change lineages , 2009, Nature.

[30]  Jun Pang,et al.  ASSA-PBN: A Toolbox for Probabilistic Boolean Networks , 2018, IEEE/ACM Transactions on Computational Biology and Bioinformatics.

[31]  S. Agarwal Cellular Reprogramming , 2008, Science.

[32]  M. Boerries,et al.  Boolean Modeling Reveals the Necessity of Transcriptional Regulation for Bistability in PC12 Cell Differentiation , 2016, Front. Genet..

[33]  S. P. Cornelius,et al.  Realistic control of network dynamics , 2013, Nature Communications.

[34]  Ion Petre,et al.  Target Controllability of Linear Networks , 2016, CMSB.

[35]  F. Müller,et al.  Few inputs can reprogram biological networks , 2011, Nature.

[36]  Réka Albert,et al.  Cell Fate Reprogramming by Control of Intracellular Network Dynamics , 2014, PLoS Comput. Biol..

[37]  Fabian J Theis,et al.  Hierarchical Differentiation of Myeloid Progenitors Is Encoded in the Transcription Factor Network , 2011, PloS one.

[38]  H. Kestler,et al.  A Boolean Model of the Cardiac Gene Regulatory Network Determining First and Second Heart Field Identity , 2012, PloS one.