@article{SchwahnBeleggiaOmranianetal.2017, author = {Schwahn, Kevin and Beleggia, Romina and Omranian, Nooshin and Nikoloski, Zoran}, title = {Stoichiometric Correlation Analysis: Principles of Metabolic Functionality from Metabolomics Data}, series = {Frontiers in plant science}, volume = {8}, journal = {Frontiers in plant science}, publisher = {Frontiers Research Foundation}, address = {Lausanne}, issn = {1664-462X}, doi = {10.3389/fpls.2017.02152}, pages = {12}, year = {2017}, abstract = {Recent advances in metabolomics technologies have resulted in high-quality (time-resolved) metabolic profiles with an increasing coverage of metabolic pathways. These data profiles represent read-outs from often non-linear dynamics of metabolic networks. Yet, metabolic profiles have largely been explored with regression-based approaches that only capture linear relationships, rendering it difficult to determine the extent to which the data reflect the underlying reaction rates and their couplings. Here we propose an approach termed Stoichiometric Correlation Analysis (SCA) based on correlation between positive linear combinations of log-transformed metabolic profiles. The log-transformation is due to the evidence that metabolic networks can be modeled by mass action law and kinetics derived from it. Unlike the existing approaches which establish a relation between pairs of metabolites, SCA facilitates the discovery of higherorder dependence between more than two metabolites. By using a paradigmatic model of the tricarboxylic acid cycle we show that the higher-order dependence reflects the coupling of concentration of reactant complexes, capturing the subtle difference between the employed enzyme kinetics. Using time-resolved metabolic profiles from Arabidopsis thaliana and Escherichia coli, we show that SCA can be used to quantify the difference in coupling of reactant complexes, and hence, reaction rates, underlying the stringent response in these model organisms. By using SCA with data from natural variation of wild and domesticated wheat and tomato accession, we demonstrate that the domestication is accompanied by loss of such couplings, in these species. Therefore, application of SCA to metabolomics data from natural variation in wild and domesticated populations provides a mechanistic way to understanding domestication and its relation to metabolic networks.}, language = {en} } @article{RuprechtLohausVannesteetal.2017, author = {Ruprecht, Colin and Lohaus, Rolf and Vanneste, Kevin and Mutwil, Marek and Nikoloski, Zoran and Van de Peer, Yves and Persson, Staffan}, title = {Revisiting ancestral polyploidy in plants}, series = {Science Advances}, volume = {3}, journal = {Science Advances}, publisher = {American Assoc. for the Advancement of Science}, address = {Washington}, issn = {2375-2548}, doi = {10.1126/sciadv.1603195}, pages = {6}, year = {2017}, abstract = {Whole-genome duplications (WGDs) or polyploidy events have been studied extensively in plants. In a now widely cited paper, Jiao et al. presented evidence for two ancient, ancestral plant WGDs predating the origin of flowering and seed plants, respectively. This finding was based primarily on a bimodal age distribution of gene duplication events obtained from molecular dating of almost 800 phylogenetic gene trees. We reanalyzed the phylogenomic data of Jiao et al. and found that the strong bimodality of the age distribution may be the result of technical and methodological issues and may hence not be a "true" signal of two WGD events. By using a state-of-the-art molecular dating algorithm, we demonstrate that the reported bimodal age distribution is not robust and should be interpreted with caution. Thus, there exists little evidence for two ancient WGDs in plants from phylogenomic dating.}, language = {en} } @article{RobainaEstevezNikoloski2017, author = {Robaina-Estevez, Semidan and Nikoloski, Zoran}, title = {On the effects of alternative optima in context-specific metabolic model predictions}, series = {PLoS Computational Biology : a new community journal}, volume = {13}, journal = {PLoS Computational Biology : a new community journal}, publisher = {PLoS}, address = {San Fransisco}, issn = {1553-734X}, doi = {10.1371/journal.pcbi.1005568}, pages = {750 -- 766}, year = {2017}, abstract = {The integration of experimental data into genome-scale metabolic models can greatly improve flux predictions. This is achieved by restricting predictions to a more realistic context-specific domain, like a particular cell or tissue type. Several computational approaches to integrate data have been proposed D generally obtaining context-specific (sub) models or flux distributions. However, these approaches may lead to a multitude of equally valid but potentially different models or flux distributions, due to possible alternative optima in the underlying optimization problems. Although this issue introduces ambiguity in context-specific predictions, it has not been generally recognized, especially in the case of model reconstructions. In this study, we analyze the impact of alternative optima in four state-of-the-art context-specific data integration approaches, providing both flux distributions and/or metabolic models. To this end, we present three computational methods and apply them to two particular case studies: leaf-specific predictions from the integration of gene expression data in a metabolic model of Arabidopsis thaliana, and liver-specific reconstructions derived from a human model with various experimental data sources. The application of these methods allows us to obtain the following results: (i) we sample the space of alternative flux distributions in the leaf-and the liver-specific case and quantify the ambiguity of the predictions. In addition, we show how the inclusion of l(1)-regularization during data integration reduces the ambiguity in both cases. (ii) We generate sets of alternative leaf-and liver-specific models that are optimal to each one of the evaluated model reconstruction approaches. We demonstrate that alternative models of the same context contain a marked fraction of disparate reactions. Further, we show that a careful balance between model sparsity and metabolic functionality helps in reducing the discrepancies between alternative models. Finally, our findings indicate that alternative optima must be taken into account for rendering the context-specific metabolic model predictions less ambiguous.}, language = {en} } @article{RobainaEstevezDalosoZhangetal.2017, author = {Robaina-Estevez, Semidan and Daloso, Danilo M. and Zhang, Youjun and Fernie, Alisdair R. and Nikoloski, Zoran}, title = {Resolving the central metabolism of Arabidopsis guard cells}, series = {Scientific reports}, volume = {7}, journal = {Scientific reports}, publisher = {Nature Publ. Group}, address = {London}, issn = {2045-2322}, doi = {10.1038/s41598-017-07132-9}, pages = {1913 -- 1932}, year = {2017}, abstract = {Photosynthesis and water use efficiency, key factors affecting plant growth, are directly controlled by microscopic and adjustable pores in the leaf-the stomata. The size of the pores is modulated by the guard cells, which rely on molecular mechanisms to sense and respond to environmental changes. It has been shown that the physiology of mesophyll and guard cells differs substantially. However, the implications of these differences to metabolism at a genome-scale level remain unclear. Here, we used constraint-based modeling to predict the differences in metabolic fluxes between the mesophyll and guard cells of Arabidopsis thaliana by exploring the space of fluxes that are most concordant to cell-type-specific transcript profiles. An independent C-13-labeling experiment using isolated mesophyll and guard cells was conducted and provided support for our predictions about the role of the Calvin-Benson cycle in sucrose synthesis in guard cells. The combination of in silico with in vivo analyses indicated that guard cells have higher anaplerotic CO2 fixation via phosphoenolpyruvate carboxylase, which was demonstrated to be an important source of malate. Beyond highlighting the metabolic differences between mesophyll and guard cells, our findings can be used in future integrated modeling of multicellular plant systems and their engineering towards improved growth.}, language = {en} } @article{HansenMeyerFerrarietal.2017, author = {Hansen, Bjoern Oest and Meyer, Etienne H. and Ferrari, Camilla and Vaid, Neha and Movahedi, Sara and Vandepoele, Klaas and Nikoloski, Zoran and Mutwil, Marek}, title = {Ensemble gene function prediction database reveals genes important for complex I formation in Arabidopsis thaliana}, series = {New phytologist : international journal of plant science}, volume = {217}, journal = {New phytologist : international journal of plant science}, number = {4}, publisher = {Wiley}, address = {Hoboken}, issn = {0028-646X}, doi = {10.1111/nph.14921}, pages = {1521 -- 1534}, year = {2017}, abstract = {Recent advances in gene function prediction rely on ensemble approaches that integrate results from multiple inference methods to produce superior predictions. Yet, these developments remain largely unexplored in plants. We have explored and compared two methods to integrate 10 gene co-function networks for Arabidopsis thaliana and demonstrate how the integration of these networks produces more accurate gene function predictions for a larger fraction of genes with unknown function. These predictions were used to identify genes involved in mitochondrial complex I formation, and for five of them, we confirmed the predictions experimentally. The ensemble predictions are provided as a user-friendly online database, EnsembleNet. The methods presented here demonstrate that ensemble gene function prediction is a powerful method to boost prediction performance, whereas the EnsembleNet database provides a cutting-edge community tool to guide experimentalists.}, language = {en} } @misc{BreuerNowakIvakovetal.2017, author = {Breuer, David and Nowak, Jacqueline and Ivakov, Alexander and Somssich, Marc and Persson, Staffan and Nikoloski, Zoran}, title = {System-wide organization of actin cytoskeleton determines organelle transport in hypocotyl plant cells}, series = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {114}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, publisher = {National Acad. of Sciences}, address = {Washington}, issn = {0027-8424}, doi = {10.1073/pnas.1712371114}, pages = {E6732 -- E6732}, year = {2017}, language = {en} } @article{BreuerNowakIvakovetal.2017, author = {Breuer, David and Nowak, Jacqueline and Ivakov, Alexander and Somssich, Marc and Persson, Staffan and Nikoloski, Zoran}, title = {System-wide organization of actin cytoskeleton determines organelle transport in hypocotyl plant cells}, series = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {114}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, publisher = {National Acad. of Sciences}, address = {Washington}, issn = {0027-8424}, doi = {10.1073/pnas.1706711114}, pages = {E5741 -- E5749}, year = {2017}, abstract = {The actin cytoskeleton is an essential intracellular filamentous structure that underpins cellular transport and cytoplasmic streaming in plant cells. However, the system-level properties of actin-based cellular trafficking remain tenuous, largely due to the inability to quantify key features of the actin cytoskeleton. Here, we developed an automated image-based, network-driven framework to accurately segment and quantify actin cytoskeletal structures and Golgi transport. We show that the actin cytoskeleton in both growing and elongated hypocotyl cells has structural properties facilitating efficient transport. Our findings suggest that the erratic movement of Golgi is a stable cellular phenomenon that might optimize distribution efficiency of cell material. Moreover, we demonstrate that Golgi transport in hypocotyl cells can be accurately predicted from the actin network topology alone. Thus, our framework provides quantitative evidence for system-wide coordination of cellular transport in plant cells and can be readily applied to investigate cytoskeletal organization and transport in other organisms.}, language = {en} } @article{ApeltBreuerOlasetal.2017, author = {Apelt, Federico and Breuer, David and Olas, Justyna Jadwiga and Annunziata, Maria Grazia and Flis, Anna and Nikoloski, Zoran and Kragler, Friedrich and Stitt, Mark}, title = {Circadian, Carbon, and Light Control of Expansion Growth and Leaf Movement}, series = {Plant physiology : an international journal devoted to physiology, biochemistry, cellular and molecular biology, biophysics and environmental biology of plants}, volume = {174}, journal = {Plant physiology : an international journal devoted to physiology, biochemistry, cellular and molecular biology, biophysics and environmental biology of plants}, publisher = {American Society of Plant Physiologists}, address = {Rockville}, issn = {0032-0889}, doi = {10.1104/pp.17.00503}, pages = {1949 -- 1968}, year = {2017}, language = {en} }