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Derivation, identification and validation of a computational model of a novel synthetic regulatory network in yeast

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Abstract

Systems biology aims at building computational models of biological pathways in order to study in silico their behaviour and to verify biological hypotheses. Modelling can become a new powerful method in molecular biology, if correctly used. Here we present step-by-step the derivation and identification of the dynamical model of a biological pathway using a novel synthetic network recently constructed in the yeast Saccharomyces cerevisiae for In-vivo Reverse-Engineering and Modelling Assessment. This network consists of five genes regulating each other transcription. Moreover, it includes one protein–protein interaction, and its genes can be switched on by addition of galactose to the medium. In order to describe the network dynamics, we adopted a deterministic modelling approach based on non-linear differential equations. We show how, through iteration between experiments and modelling, it is possible to derive a semi-quantitative prediction of network behaviour and to better understand the biology of the pathway of interest.

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References

  • Alon U (2006) An Introduction to systems biology: design principles of biological circuits. Chapman & Hall, London

    MATH  Google Scholar 

  • Anders A, Lilie H, Franke K, Kapp L, Stelling J, Gilles ED, Breunig KD (2006) The galactose switch in kluyveromyces lactis depends on nuclear competition between gal4 and gal1 for gal80 binding. J Biol Chem 281(39): 29337–29348

    Article  Google Scholar 

  • Anderson J, Papachristodoulou A (2009) On validation and invalidation of biological models. BMC Bioinform 10: 132

    Article  Google Scholar 

  • Arlot S, Celisse A (2010) A survey of cross-validation procedures for model selection. Stat Surv 4: 40–79

    Article  MATH  MathSciNet  Google Scholar 

  • Bennett MR, Pang WL, Ostroff NA, Baumgartner BL, Nayak S, Tsimring LS, Hasty J (2008) Metabolic gene regulation in a dynamically changing environment. Nature 454: 1119–1122

    Article  Google Scholar 

  • Bhoite LT, Yu Y, Stillman DJ (2001) The swi5 activator recruits the mediator complex to the ho promoter without rna polymerase II. Genes Dev 15: 2457–2469

    Article  Google Scholar 

  • Bogacki P, Shampine LF (1989) A 3(2) pair of Runge–Kutta formulas. Appl Numer Math 2: 1–9

    MathSciNet  Google Scholar 

  • Boubaker O, Fourati A (2004) Structural identifiability of non linear systems: an overview. Ind Technol 3: 1224–1248

    Google Scholar 

  • Cantone I, Marucci L, Iorio F, Ricci MA, Belcastro V, Bansal M, di Bernardo M, Santini S, di Bernardo D, Cosma MP (2009) A yeast synthetic network for in vivo assessment of reverse-engineering and modeling approaches. Cell 137: 171–181

    Article  Google Scholar 

  • Cobelli C, Distefano JJ III (1980) Parameter and structural identifiability concepts and ambiguities: a critical review and analysis. Am J Physiol 239: R7–R24

    Google Scholar 

  • Copeland R (2000) Enzymes: a practical introduction to structure, mechanism, and data analysis, 2nd edn. Wiley, New York

    Google Scholar 

  • Cosma MP, Tanaka T, Nasmyth K (1999) Ordered recruitment of transcription and chromatin remodeling factors to a cell cycle and developmentally regulated promoter. Cell 97: 299–311

    Article  Google Scholar 

  • De Jong H (2002) Modeling and simulation of genetic regulatory systems: a literature review. J Comput Biol 9: 67–103

    Article  Google Scholar 

  • Elowitz MB, Leibler S (2000) A synthetic oscillatory network of transcriptional regulators. Nature 403(6767): 335–338

    Article  Google Scholar 

  • Gardner TS, Cantor CR, Collins JJ (2000) Construction of a genetic toggle switch in Escherichia coli. Nature 403(6767): 339–342

    Article  Google Scholar 

  • Giniger E, Ptashne M (1988) Cooperative dna binding of the yeast transcriptional activator gal4. Proc Natl Acad Sci 85: 382–386

    Article  Google Scholar 

  • Hatzimanikatis V, Lee KH (1999) Dynamical analysis of gene networks requires both mRNA and protein expression information. Metabol Eng 1(4): 275–281

    Article  Google Scholar 

  • Hemmerich P, Stoyan T, Wieland G, Koch M, Lechner J, Diekmann S (2000) Interaction of yeast kinetochore proteins with centromere-proteinytranscription factor cbf1. Proc Natl Acad Sci USA 97(23): 12583–12588

    Article  Google Scholar 

  • Jona G, Choder M, Gileadi O (2000) Glucose starvation induces a drastic reduction in the rates of both transcription and degradation of mrna in yeast. Biochim Biophy Acta 1491: 37–48

    Google Scholar 

  • Kaern M, Blake WJ, Collins JJ (2003) The engineering of gene regulatory networks. Annu Rev Biomed Eng 5: 179–206

    Article  Google Scholar 

  • Kaznessis Y (2007) Models for synthetic biology. BMC Syst Biol 1(1): 47

    Article  Google Scholar 

  • Kramer BP, Viretta AU, Daoud-El-Baba M, Aubel D, Weber W, Fussenegger M (2004) An engineered epigenetic transgene switch in mammalian cells. Nat Biotechnol 22(7): 867–870

    Article  Google Scholar 

  • Kumar A, Daoutidis P (1999) Control of nonlinear differential algebraic equation systems: with application to chemical processes. CRC Press, West Palm Beach

    MATH  Google Scholar 

  • Ljung L (1998) System identification: theory for the user, 2nd edn. Prentice-Hall, Englewood Cliffs

    Google Scholar 

  • Maiwald T, Timmer J (2008) Dynamical modeling and multi-experiment fitting with potterswheel. Bioinformatics 24(18): 2037–2043

    Article  Google Scholar 

  • Mangan S, Alon U (2003) Structure and function of the feed-forward loop network motif. Proc Natl Acad Sci USA 100(21): 11980–11985

    Article  Google Scholar 

  • Mitchell M (1998) An introduction to genetic algorithms (complex adaptive systems). MIT Press, Cambridge

    Google Scholar 

  • Moles CG, Mendes P, Banga JR (2003) Parameter estimation in biochemical pathways: a comparison of global optimization methods. Genome Res 13(11): 2467–2474

    Article  Google Scholar 

  • Muratani M, Kung C, Shokat KM, Tansey WP (2005) The f box protein dsg1/mdm30 is a transcriptional coactivator that stimulates gal4 turnover and cotranscriptional mrna processing. Cell 120: 887–899

    Article  Google Scholar 

  • Nelles O (2000) Nonlinear system identification: from classical approaches to neural networks and fuzzy models, 1st edn. Springer, Berlin

    Google Scholar 

  • Raue A, Kreutz C, Maiwald T, Bachmann J, Schilling M, Klingmuller U, Timmer J (2009) Structural and practical identifiability analysis of partially observed dynamical models by exploiting the profile likelihood. Bioinformatics 25(15): 1923–1929

    Article  Google Scholar 

  • Ro D-K, Paradise EM, Ouellet M, Fisher KJ, Newman KL, Ndungu JM, Ho KA, Eachus RA, Ham TS, Kirby J, Chang MCY, Withers ST, Shiba Y, Sarpong R, Keasling JD (2006) Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature 440(7086): 940–943

    Article  Google Scholar 

  • Shampine LF, Thompson S (2001) Solving ddes in matlab. Appl Numer Math 37: 441–458

    Article  MATH  MathSciNet  Google Scholar 

  • Smith RS, Doyle JC (1992) Model validation: a connection between robust control and identification. IEEE Trans Automat Contr 37: 942–952

    Article  MATH  MathSciNet  Google Scholar 

  • Stricker J, Cookson S, Bennett MRR, Mather WHH, Tsimring LSS, Hasty J (2008) A fast, robust and tunable synthetic gene oscillator. Nature 456(7221): 516–519

    Article  Google Scholar 

  • Szallasi Z, Stelling J, Periwal V (2006) System modeling in cellular biology: from concepts to nuts and bolts. MIT Press, Cambridge

    Google Scholar 

  • Tigges M, Marquez-Lago TT, Stelling J, Fussenegger M (2009) A tunable synthetic mammalian oscillator. Nature 457(7227): 309–312

    Article  Google Scholar 

  • Ventura BD, Lemerle C, Michalodimitrakis K, Serrano L (2006) From in vivo to in silico biology and back. Nature 443: 527–533

    Article  Google Scholar 

  • Verma M, Bhat JP, Venkatesh KV (2004) Quantitative analysis of gal genetic switch of Saccharomyces cerevisiae reveals that nucleocytoplasmic shuttling of gal80p results in a highly sensitive response to galactose. J Biol Chem 278: 48764–48769

    Article  Google Scholar 

  • Walter E, Pronzato L (1997) Identification of parametric models from experimental data. Springer, Berlin

    MATH  Google Scholar 

  • Weber W, Stelling J, Rimann M, Keller B, Baba MDE, Weber CC, Aubel D, Fussenegger M (2007) A synthetic time-delay circuit in mammalian cells and mice. Proc Natl Acad Sci USA 104(8): 2643–2648

    Article  Google Scholar 

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Correspondence to Lucia Marucci.

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Marucci, L., Santini, S., di Bernardo, M. et al. Derivation, identification and validation of a computational model of a novel synthetic regulatory network in yeast. J. Math. Biol. 62, 685–706 (2011). https://doi.org/10.1007/s00285-010-0350-z

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  • DOI: https://doi.org/10.1007/s00285-010-0350-z

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