Mosaic gene network modelling identified new regulatory mechanisms in HCV infection.
Modelling of gene networks is widely used in systems biology to study the functioning of complex biological systems. Most of the existing mathematical modelling techniques are useful for analysis of well-studied biological processes, for which information on rates of reactions is available. However, complex biological processes such as those determining the phenotypic traits of organisms or pathological disease processes, including pathogen-host interactions, involve complicated cross-talk between interacting networks. Furthermore, the intrinsic details of the interactions between these networks are often missing. In this study, we developed an approach, which we call mosaic network modelling, that allows the combination of independent mathematical models of gene regulatory networks and, thereby, description of complex biological systems. The advantage of this approach is that it allows us to generate the integrated model despite the fact that information on molecular interactions between parts of the model (so-called mosaic fragments) might be missing. To generate a mosaic mathematical model, we used control theory and mathematical models, written in the form of a system of ordinary differential equations (ODEs). In the present study, we investigated the efficiency of this method in modelling the dynamics of more than 10,000 simulated mosaic regulatory networks consisting of two pieces. Analysis revealed that this approach was highly efficient, as the mean deviation of the dynamics of mosaic network elements from the behaviour of the initial parts of the model was less than 10%. It turned out that for construction of the control functional, data on perturbation of one or two vertices of the mosaic piece are sufficient. Further, we used the developed method to construct a mosaic gene regulatory network including hepatitis C virus (HCV) as the first piece and the tumour necrosis factor (TNF)-induced apoptosis and NF-κB induction pathways as the second piece. Thus, the mosaic model integrates the model of HCV subgenomic replicon replication with the model of TNF-induced apoptosis and NF-κB induction. Analysis of the mosaic model revealed that the regulation of TNF-induced signaling by the HCV network is crucially dependent on the RIP1, TRADD, TRAF2, FADD, IKK, IκBα, c-FLIP, and BAR genes. Overall, the developed mosaic gene network modelling approach demonstrated good predictive power and allowed the prediction of new regulatory nodes in HCV action on apoptosis and the NF-κB pathway. Those theoretical predictions could be a basis for further experimental verification.
The Federal Research Center Institute of Cytology and Genetics, The Siberian Branch of the Russian Academy of Sciences, Prospekt Lavrentyeva 10, Novosibirsk 630090, Russia.
Olga V
OV
Popik
The Federal Research Center Institute of Cytology and Genetics, The Siberian Branch of the Russian Academy of Sciences, Prospekt Lavrentyeva 10, Novosibirsk 630090, Russia; International Tomography Center SB RAS, Institutskaya 3A, Novosibirsk 630090, Russia.
Evgeny D
ED
Petrovskiy
The Federal Research Center Institute of Cytology and Genetics, The Siberian Branch of the Russian Academy of Sciences, Prospekt Lavrentyeva 10, Novosibirsk 630090, Russia.
Elena L
EL
Mishchenko
The Federal Research Center Institute of Cytology and Genetics, The Siberian Branch of the Russian Academy of Sciences, Prospekt Lavrentyeva 10, Novosibirsk 630090, Russia; Otto von Guericke University Magdeburg, Medical Faculty, Department Translational Inflammation Research, Pfälzer Platz Building 28, Magdeburg 39106, Germany.
Inna N
IN
Lavrik
The Federal Research Center Institute of Cytology and Genetics, The Siberian Branch of the Russian Academy of Sciences, Prospekt Lavrentyeva 10, Novosibirsk 630090, Russia; PB-soft, LLC, Novosibirsk, Prospekt Lavrentyeva 10, Novosibirsk 630090, Russia. Electronic address: salix@bionet.nsc.ru.
Vladimir A
VA
Ivanisenko
D020169:Caspases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D016174:Hepacivirus / Q000235:genetics* / Q000378:metabolism; D006526:Hepatitis C / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D022781:Hepatocytes / Q000378:metabolism / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D008957:Models, Genetic; D000072000:NF-KappaB Inhibitor alpha / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D025941:Protein Interaction Mapping; D049490:Systems Biology / Q000379:methods; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism
D016328:NF-kappa B; C101338:PSMD2 protein, human; C498143:RELA protein, human; D047992:TNF Receptor-Associated Factor 2; D051996:Transcription Factor RelA; D014764:Viral Proteins; D000072000:NF-KappaB Inhibitor alpha; D020169:Caspases
Apoptosis; Hepatitis C virus; Mathematical modeling; Mosaic gene network; Tumor necrosis factor