Background Data

In previous, it was shown that integration of comprehensive gene expression profile with targeted metabolite analysis is an innovative way for identification of gene function. This will be true for in silico analysis of C. reinhardtii. In literature there are numbers of work done on C. reinhardtii. For example, Vischi Winck et al. identified regulatory elements and reconstructed gene regulatory networks of the green C. reinhardtii under carbon deprivation [1]. Lv et al. did transcriptome analysis of C. reinhardtii during the process of lipid accumulation [2]. Lee and Fiehn showed metabolomic response of C. reinhardtii to the inhibition of target of rapamycin (TOR) by rapamycin [3]. Heiland et al. modeled temperature entrainment of circadian clocks using the Arrhenius equation and a reconstructed model from C. reinhardtii [4]. Fang et al. showed transcriptome-wide changes in C. reinhardtii gene expression regulated by carbon dioxide and the CO2-concentrating mechanism regulator CIA5/CCM1[5]. Eckardt et al. analyzed gene regulatory networks of the carbon-concentrating mechanism in C. reinhardtii [6]. Toepel et al. constructed a whole genome microarray of C. reinhardtii [7]. Chang et al. reconstructed a metabolic network of C. reinhardtii which offers insight into light-driven algal metabolism [8]. Gonzalez-Ballester et al. did RNA-seq analysis of sulfur-deprived C. reinhardtii cells that reveals aspects of acclimation critical for cell survival [9]. May et al. provided an integrative systems biology database and web-portal (ChlamyCyc) for C. reinhardtii [10], but they have several limitations such as ClamyCyc is a metabolic pathway data base which did not included

transcriptional regulatory events to the best of our knowledge, their latest version 3.5 which contains 349 pathway did not includ current literatures for example the pathway hydrogen production VIII and hydrogen production included literature based on C. reinhardtii prior to 2010, any model was not presented that could be simulated or ClamyCyc lacks current information for simulation a model, some of their pathway results unexpected internal error, etc. Matthew et al. built a metabolome of C. reinhardtii following induction of anaerobic H2 production by sulfur depletion [11]. Lee do et al. also provided a high quality metabolomic data for C. reinhardtii [12]. Patel et al. showed differential gene expression of C. reinhardtii in response to 2,4,6-trinitrotoluene (TNT) using microarray analysis [13]. So far complete picture of global regulatory and metabolic map of C. reinhardtii is missing. There is still lack in integration of transcriptomic and metabolomic data of C. reinhardtii. This research will take an attempt to fulfill this ambitious project.

Currently available algorithms such as FBA (Flux balance analysis)- driven algorithm (such as GIMME, iMAT, E.Flux, MADE, PROM etc.) for integrating expression data into genome-scale network reconstructions [14], Integrative Omics-Metabolic Analysis (IOMA) which integrates metabolomics data and proteomics data, Mass Action Stoichiometric Simulation (MASS) which uses metabolomic, fluxomic, and proteomic data and the Model-Building Algorithm (MBA) which utilizes literature-based knowledge, transcriptomic, proteomic, metabolomic, and phenotypic data to curate network reconstruction [15-17] will be taken into account. In a recent study, a method called Integrated Molecular Pathway-Level Analysis (IMPaLA) for the integrated analysis of transcriptomic and metabolomic data was proposed that exploits the fact that genes and metabolites are linked through biochemical reactions and thus are contained in many pathways [20]. Another method such as OnPLS can handle noisy, multicollinear datasets from multiple platforms including transcriptomics (microarray analysis), proteomics (UPLC/QTOFMS), and metabolomics (GC-TOF/MS, UPLC/MS, and UHPLC-LTQ/MS) based on the most recent development of orthogonal projections to latent structures [21]. In another study a webbased systems biology tool called 3Omics is used for analysis, integration and visualization of human transcriptomic, proteomic and metabolomic data [22]. A better method will be followed to minimize the limitation of currently available methods and tools This project will follow the bottom up approach of model building which combines all organism specific information into a complete genome-scale model to provide an integrative view of the biological interactions occurring inside C. reinhardtii. Constraint-based modeling is one of the widely accepted approaches for mathematical modeling [18] which is the core of bottom-up approach. Both stochastic and deterministic modeling approaches will be exploited in this project. Stochastic models often require more computational work for simulation whereas deterministic models usually require less computational work involved in systems of differential equations, though stochastic models can reflect the environmental and demographic variables that is prevalent in biological systems [19].

Web link
Complete and Reference proteome http://www.uniprot.org/taxonomy/3055 Information and links
http://www.chlamy.org/

http://chlamycollection.org/ Genome http://www.ncbi.nlm.nih.gov/genome/147 GEO dataset http://www.ncbi.nlm.nih.gov/gds/?term=chlamydomonas Bioproject http://www.ncbi.nlm.nih.gov/bioproject/?term=Chlamydomonas Chlamydomonas reinhardtii Transcription factors (348 protein models) http://plntfdb.bio.uni-potsdam.de/v3.0/index.php?sp_id=CRE4 Metabolic data and Pathways http://pmn.plantcyc.org/PLANT/NEW-IMAGE?type=ORGANISM&object=CHLAMY

References
1. Vischi Winck, F., et al., Genome-wide identification of regulatory elements and reconstruction of gene regulatory networks of the green alga Chlamydomonas reinhardtii under carbon deprivation. PLoS One, 2013. 8(11): p. e79909. Lv, H., et al., Transcriptome analysis of Chlamydomonas reinhardtii during the process of lipid accumulation. Genomics, 2013. 101(4): p. 229-37. Lee do, Y. and O. Fiehn, Metabolomic response of chlamydomonas reinhardtii to the inhibition of target of rapamycin (TOR) by rapamycin. J Microbiol Biotechnol, 2013. 23(7): p. 923-31. Heiland, I., et al., Modeling temperature entrainment of circadian clocks using the Arrhenius equation and a reconstructed model from Chlamydomonas reinhardtii. J Biol Phys, 2012. 38(3): p. 449-64. Fang, W., et al., Transcriptome-wide changes in Chlamydomonas reinhardtii gene expression regulated by carbon dioxide and the CO2-concentrating mechanism regulator CIA5/CCM1. Plant Cell, 2012. 24(5): p. 1876-93. 3

2. 3. 4.

5.

6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.

21.

22.

Eckardt, N.A., Gene Regulatory Networks of the Carbon-Concentrating Mechanism in Chlamydomonas reinhardtii. The Plant Cell, 2012. 24(5): p. 1713-1713. Toepel, J., et al., Construction and evaluation of a whole genome microarray of Chlamydomonas reinhardtii. BMC Genomics, 2011. 12: p. 579. Chang, R.L., et al., Metabolic network reconstruction of Chlamydomonas offers insight into lightdriven algal metabolism. Mol Syst Biol, 2011. 7: p. 518. Gonzalez-Ballester, D., et al., RNA-seq analysis of sulfur-deprived Chlamydomonas cells reveals aspects of acclimation critical for cell survival. Plant Cell, 2010. 22(6): p. 2058-84. May, P., et al., ChlamyCyc: an integrative systems biology database and web-portal for Chlamydomonas reinhardtii. BMC Genomics, 2009. 10: p. 209. Matthew, T., et al., The metabolome of Chlamydomonas reinhardtii following induction of anaerobic H2 production by sulfur depletion. J Biol Chem, 2009. 284(35): p. 23415-25. Lee do, Y. and O. Fiehn, High quality metabolomic data for Chlamydomonas reinhardtii. Plant Methods, 2008. 4: p. 7. Patel, N., et al., Differential gene expression of Chlamydomonas reinhardtii in response to 2,4,6trinitrotoluene (TNT) using microarray analysis. Plant Science, 2004. 167(5): p. 1109-1122. Blazier, A.S. and J.A. Papin, Integration of expression data in genome-scale metabolic network reconstructions. Front Physiol, 2012. 3: p. 299. Yizhak, K., et al., Integrating quantitative proteomics and metabolomics with a genome-scale metabolic network model. Bioinformatics, 2010. 26(12): p. i255-60. Jamshidi, N. and B.O. Palsson, Mass action stoichiometric simulation models: incorporating kinetics and regulation into stoichiometric models. Biophys J, 2010. 98(2): p. 175-85. Jerby, L., T. Shlomi, and E. Ruppin, Computational reconstruction of tissue-specific metabolic models: application to human liver metabolism. Mol Syst Biol, 2010. 6: p. 401. Price, N.D., J.L. Reed, and B.O. Palsson, Genome-scale models of microbial cells: evaluating the consequences of constraints. Nat Rev Microbiol, 2004. 2(11): p. 886-97. Murray, J.D., Vignettes from the field of mathematical biology: the application of mathematics to biology and medicine. Interface Focus, 2012. 2(4): p. 397-406. Cavill, R., et al., Consensus-phenotype integration of transcriptomic and metabolomic data implies a role for metabolism in the chemosensitivity of tumour cells. PLoS Comput Biol, 2011. 7(3): p. e1001113. Srivastava, V., et al., OnPLS integration of transcriptomic, proteomic and metabolomic data shows multi-level oxidative stress responses in the cambium of transgenic hipI- superoxide dismutase Populus plants. BMC Genomics, 2013. 14: p. 893. Kuo, T.C., T.F. Tian, and Y.J. Tseng, 3Omics: a web-based systems biology tool for analysis, integration and visualization of human transcriptomic, proteomic and metabolomic data. BMC Syst Biol, 2013. 7: p. 64.