@article{ZakharovaNikoloskiKoseska2013, author = {Zakharova, A. and Nikoloski, Zoran and Koseska, Aneta}, title = {Dimensionality reduction of bistable biological systems}, series = {Bulletin of mathematical biology : official journal of the Society for Mathematical Biology}, volume = {75}, journal = {Bulletin of mathematical biology : official journal of the Society for Mathematical Biology}, number = {3}, publisher = {Springer}, address = {New York}, issn = {0092-8240}, doi = {10.1007/s11538-013-9807-8}, pages = {373 -- 392}, year = {2013}, abstract = {Time hierarchies, arising as a result of interactions between system's components, represent a ubiquitous property of dynamical biological systems. In addition, biological systems have been attributed switch-like properties modulating the response to various stimuli across different organisms and environmental conditions. Therefore, establishing the interplay between these features of system dynamics renders itself a challenging question of practical interest in biology. Existing methods are suitable for systems with one stable steady state employed as a well-defined reference. In such systems, the characterization of the time hierarchies has already been used for determining the components that contribute to the dynamics of biological systems. However, the application of these methods to bistable nonlinear systems is impeded due to their inherent dependence on the reference state, which in this case is no longer unique. Here, we extend the applicability of the reference-state analysis by proposing, analyzing, and applying a novel method, which allows investigation of the time hierarchies in systems exhibiting bistability. The proposed method is in turn used in identifying the components, other than reactions, which determine the systemic dynamical properties. We demonstrate that in biological systems of varying levels of complexity and spanning different biological levels, the method can be effectively employed for model simplification while ensuring preservation of qualitative dynamical properties (i.e., bistability). Finally, by establishing a connection between techniques from nonlinear dynamics and multivariate statistics, the proposed approach provides the basis for extending reference-based analysis to bistable systems.}, language = {en} } @article{YuWuNowaketal.2019, author = {Yu, Yanjun and Wu, Shenjie and Nowak, Jacqueline and Wang, Guangda and Han, Libo and Feng, Zhidi and Mendrinna, Amelie and Ma, Yinping and Wang, Huan and Zhang, Xiaxia and Tian, Juan and Dong, Li and Nikoloski, Zoran and Persson, Staffan and Kong, Zhaosheng}, title = {Live-cell imaging of the cytoskeleton in elongating cotton fibres}, series = {Nature plants}, volume = {5}, journal = {Nature plants}, number = {5}, publisher = {Nature Publ. Group}, address = {London}, issn = {2055-026X}, doi = {10.1038/s41477-019-0418-8}, pages = {498 -- 504}, year = {2019}, abstract = {Cotton (Gossypium hirsutum) fibres consist of single cells that grow in a highly polarized manner, assumed to be controlled by the cytoskeleton(1-3). However, how the cytoskeletal organization and dynamics underpin fibre development remains unexplored. Moreover, it is unclear whether cotton fibres expand via tip growth or diffuse growth(2-4). We generated stable transgenic cotton plants expressing fluorescent markers of the actin and microtubule cytoskeleton. Live-cell imaging revealed that elongating cotton fibres assemble a cortical filamentous actin network that extends along the cell axis to finally form actin strands with closed loops in the tapered fibre tip. Analyses of F-actin network properties indicate that cotton fibres have a unique actin organization that blends features of both diffuse and tip growth modes. Interestingly, typical actin organization and endosomal vesicle aggregation found in tip-growing cell apices were not observed in fibre tips. Instead, endomembrane compartments were evenly distributed along the elongating fibre cells and moved bi-directionally along the fibre shank to the fibre tip. Moreover, plus-end tracked microtubules transversely encircled elongating fibre shanks, reminiscent of diffusely growing cells. Collectively, our findings indicate that cotton fibres elongate via a unique tip-biased diffuse growth mode.}, language = {en} } @article{XuRazaghiMoghadamNikoloski2021, author = {Xu, Rudan and Razaghi-Moghadam, Zahra and Nikoloski, Zoran}, title = {Maximization of non-idle enzymes improves the coverage of the estimated maximal in vivo enzyme catalytic rates in Escherichia coli}, series = {Bioinformatics}, volume = {37}, journal = {Bioinformatics}, number = {21}, publisher = {Oxford Univ. Press}, address = {Oxford}, issn = {1367-4803}, doi = {10.1093/bioinformatics/btab575}, pages = {3848 -- 3855}, year = {2021}, abstract = {Motivation: Constraint-based modeling approaches allow the estimation of maximal in vivo enzyme catalytic rates that can serve as proxies for enzyme turnover numbers. Yet, genome-scale flux profiling remains a challenge in deploying these approaches to catalogue proxies for enzyme catalytic rates across organisms. Results: Here, we formulate a constraint-based approach, termed NIDLE-flux, to estimate fluxes at a genome-scale level by using the principle of efficient usage of expressed enzymes. Using proteomics data from Escherichia coli, we show that the fluxes estimated by NIDLE-flux and the existing approaches are in excellent qualitative agreement (Pearson correlation > 0.9). We also find that the maximal in vivo catalytic rates estimated by NIDLE-flux exhibits a Pearson correlation of 0.74 with in vitro enzyme turnover numbers. However, NIDLE-flux results in a 1.4-fold increase in the size of the estimated maximal in vivo catalytic rates in comparison to the contenders. Integration of the maximum in vivo catalytic rates with publically available proteomics and metabolomics data provide a better match to fluxes estimated by NIDLE-flux. Therefore, NIDLE-flux facilitates more effective usage of proteomics data to estimate proxies for kcatomes.}, language = {en} } @article{WinckArvidssonMauricioRianoPachonetal.2013, author = {Winck, Flavia Vischi and Arvidsson, Samuel Janne and Mauricio Riano-Pachon, Diego and Hempel, Sabrina and Koseska, Aneta and Nikoloski, Zoran and Urbina Gomez, David Alejandro and Rupprecht, Jens and M{\"u}ller-R{\"o}ber, Bernd}, title = {Genome-wide identification of regulatory elements and reconstruction of gene regulatory networks of the green alga chlamydomonas reinhardtii under carbon deprivation}, series = {PLoS one}, volume = {8}, journal = {PLoS one}, number = {11}, publisher = {PLoS}, address = {San Fransisco}, issn = {1932-6203}, doi = {10.1371/journal.pone.0079909}, pages = {16}, year = {2013}, abstract = {The unicellular green alga Chlamydomonas reinhardtii is a long-established model organism for studies on photosynthesis and carbon metabolism-related physiology. Under conditions of air-level carbon dioxide concentration [CO2], a carbon concentrating mechanism (CCM) is induced to facilitate cellular carbon uptake. CCM increases the availability of carbon dioxide at the site of cellular carbon fixation. To improve our understanding of the transcriptional control of the CCM, we employed FAIRE-seq (formaldehyde-assisted Isolation of Regulatory Elements, followed by deep sequencing) to determine nucleosome-depleted chromatin regions of algal cells subjected to carbon deprivation. Our FAIRE data recapitulated the positions of known regulatory elements in the promoter of the periplasmic carbonic anhydrase (Cah1) gene, which is upregulated during CCM induction, and revealed new candidate regulatory elements at a genome-wide scale. In addition, time series expression patterns of 130 transcription factor (TF) and transcription regulator (TR) genes were obtained for cells cultured under photoautotrophic condition and subjected to a shift from high to low [CO2]. Groups of co-expressed genes were identified and a putative directed gene-regulatory network underlying the CCM was reconstructed from the gene expression data using the recently developed IOTA (inner composition alignment) method. Among the candidate regulatory genes, two members of the MYB-related TF family, Lcr1 (Low-CO2 response regulator 1) and Lcr2 (Low-CO2 response regulator 2), may play an important role in down-regulating the expression of a particular set of TF and TR genes in response to low [CO2]. The results obtained provide new insights into the transcriptional control of the CCM and revealed more than 60 new candidate regulatory genes. Deep sequencing of nucleosome-depleted genomic regions indicated the presence of new, previously unknown regulatory elements in the C. reinhardtii genome. Our work can serve as a basis for future functional studies of transcriptional regulator genes and genomic regulatory elements in Chlamydomonas.}, language = {en} } @article{WenderingNikoloski2022, author = {Wendering, Philipp and Nikoloski, Zoran}, title = {COMMIT}, series = {PLoS Computational Biology : a new community journal / publ. by the Public Library of Science (PLoS) in association with the International Society for Computational Biology (ISCB)}, volume = {18}, journal = {PLoS Computational Biology : a new community journal / publ. by the Public Library of Science (PLoS) in association with the International Society for Computational Biology (ISCB)}, number = {3}, publisher = {Public Library of Science}, address = {San Fransisco}, issn = {1553-734X}, doi = {10.1371/journal.pcbi.1009906}, pages = {24}, year = {2022}, abstract = {Composition and functions of microbial communities affect important traits in diverse hosts, from crops to humans. Yet, mechanistic understanding of how metabolism of individual microbes is affected by the community composition and metabolite leakage is lacking. Here, we first show that the consensus of automatically generated metabolic reconstructions improves the quality of the draft reconstructions, measured by comparison to reference models. We then devise an approach for gap filling, termed COMMIT, that considers metabolites for secretion based on their permeability and the composition of the community. By applying COMMIT with two soil communities from the Arabidopsis thaliana culture collection, we could significantly reduce the gap-filling solution in comparison to filling gaps in individual reconstructions without affecting the genomic support. Inspection of the metabolic interactions in the soil communities allows us to identify microbes with community roles of helpers and beneficiaries. Therefore, COMMIT offers a versatile fully automated solution for large-scale modelling of microbial communities for diverse biotechnological applications.
Author summaryMicrobial communities are important in ecology, human health, and crop productivity. However, detailed information on the interactions within natural microbial communities is hampered by the community size, lack of detailed information on the biochemistry of single organisms, and the complexity of interactions between community members. Metabolic models are comprised of biochemical reaction networks based on the genome annotation, and can provide mechanistic insights into community functions. Previous analyses of microbial community models have been performed with high-quality reference models or models generated using a single reconstruction pipeline. However, these models do not contain information on the composition of the community that determines the metabolites exchanged between the community members. In addition, the quality of metabolic models is affected by the reconstruction approach used, with direct consequences on the inferred interactions between community members. Here, we use fully automated consensus reconstructions from four approaches to arrive at functional models with improved genomic support while considering the community composition. We applied our pipeline to two soil communities from the Arabidopsis thaliana culture collection, providing only genome sequences. Finally, we show that the obtained models have 90\% genomic support and demonstrate that the derived interactions are corroborated by independent computational predictions.}, language = {en} } @article{ToepferCaldanaGrimbsetal.2013, author = {T{\"o}pfer, Nadine and Caldana, Camila and Grimbs, Sergio and Willmitzer, Lothar and Fernie, Alisdair R. and Nikoloski, Zoran}, title = {Integration of genome-scale modeling and transcript profiling reveals metabolic pathways underlying light and temperature acclimation in arabidopsis}, series = {The plant cell}, volume = {25}, journal = {The plant cell}, number = {4}, publisher = {American Society of Plant Physiologists}, address = {Rockville}, issn = {1040-4651}, doi = {10.1105/tpc.112.108852}, pages = {1197 -- 1211}, year = {2013}, abstract = {Understanding metabolic acclimation of plants to challenging environmental conditions is essential for dissecting the role of metabolic pathways in growth and survival. As stresses involve simultaneous physiological alterations across all levels of cellular organization, a comprehensive characterization of the role of metabolic pathways in acclimation necessitates integration of genome-scale models with high-throughput data. Here, we present an integrative optimization-based approach, which, by coupling a plant metabolic network model and transcriptomics data, can predict the metabolic pathways affected in a single, carefully controlled experiment. Moreover, we propose three optimization-based indices that characterize different aspects of metabolic pathway behavior in the context of the entire metabolic network. We demonstrate that the proposed approach and indices facilitate quantitative comparisons and characterization of the plant metabolic response under eight different light and/or temperature conditions. The predictions of the metabolic functions involved in metabolic acclimation of Arabidopsis thaliana to the changing conditions are in line with experimental evidence and result in a hypothesis about the role of homocysteine-to-Cys interconversion and Asn biosynthesis. The approach can also be used to reveal the role of particular metabolic pathways in other scenarios, while taking into consideration the entirety of characterized plant metabolism.}, language = {en} } @article{TongNikoloski2020, author = {Tong, Hao and Nikoloski, Zoran}, title = {Machine learning approaches for crop improvement}, series = {Journal of plant physiology : biochemistry, physiology, molecular biology and biotechnology of plants}, volume = {257}, journal = {Journal of plant physiology : biochemistry, physiology, molecular biology and biotechnology of plants}, publisher = {Elsevier}, address = {M{\"u}nchen}, issn = {0176-1617}, doi = {10.1016/j.jplph.2020.153354}, pages = {13}, year = {2020}, abstract = {Highly efficient and accurate selection of elite genotypes can lead to dramatic shortening of the breeding cycle in major crops relevant for sustaining present demands for food, feed, and fuel. In contrast to classical approaches that emphasize the need for resource-intensive phenotyping at all stages of artificial selection, genomic selection dramatically reduces the need for phenotyping. Genomic selection relies on advances in machine learning and the availability of genotyping data to predict agronomically relevant phenotypic traits. Here we provide a systematic review of machine learning approaches applied for genomic selection of single and multiple traits in major crops in the past decade. We emphasize the need to gather data on intermediate phenotypes, e.g. metabolite, protein, and gene expression levels, along with developments of modeling techniques that can lead to further improvements of genomic selection. In addition, we provide a critical view of factors that affect genomic selection, with attention to transferability of models between different environments. Finally, we highlight the future aspects of integrating high-throughput molecular phenotypic data from omics technologies with biological networks for crop improvement.}, language = {en} } @article{TongNankarLiuetal.2022, author = {Tong, Hao and Nankar, Amol N. and Liu, Jintao and Todorova, Velichka and Ganeva, Daniela and Grozeva, Stanislava and Tringovska, Ivanka and Pasev, Gancho and Radeva-Ivanova, Vesela and Gechev, Tsanko and Kostova, Dimitrina and Nikoloski, Zoran}, title = {Genomic prediction of morphometric and colorimetric traits in Solanaceous fruits}, series = {Horticulture research}, volume = {9}, journal = {Horticulture research}, publisher = {Oxford Univ. Press}, address = {Cary}, issn = {2052-7276}, doi = {10.1093/hr/uhac072}, pages = {11}, year = {2022}, abstract = {Selection of high-performance lines with respect to traits of interest is a key step in plant breeding. Genomic prediction allows to determine the genomic estimated breeding values of unseen lines for trait of interest using genetic markers, e.g. single-nucleotide polymorphisms (SNPs), and machine learning approaches, which can therefore shorten breeding cycles, referring to genomic selection (GS). Here, we applied GS approaches in two populations of Solanaceous crops, i.e. tomato and pepper, to predict morphometric and colorimetric traits. The traits were measured by using scoring-based conventional descriptors (CDs) as well as by Tomato Analyzer (TA) tool using the longitudinally and latitudinally cut fruit images. The GS performance was assessed in cross-validations of classification-based and regression-based machine learning models for CD and TA traits, respectively. The results showed the usage of TA traits and tag SNPs provide a powerful combination to predict morphology and color-related traits of Solanaceous fruits. The highest predictability of 0.89 was achieved for fruit width in pepper, with an average predictability of 0.69 over all traits. The multi-trait GS models are of slightly better predictability than single-trait models for some colorimetric traits in pepper. While model validation performs poorly on wild tomato accessions, the usage as many as one accession per wild species in the training set can increase the transferability of models to unseen populations for some traits (e.g. fruit shape for which predictability in unseen scenario increased from zero to 0.6). Overall, GS approaches can assist the selection of high-performance Solanaceous fruits in crop breeding.}, language = {en} } @article{TongKuekenRazaghiMoghadametal.2021, author = {Tong, Hao and K{\"u}ken, Anika and Razaghi-Moghadam, Zahra and Nikoloski, Zoran}, title = {Characterization of effects of genetic variants via genome-scale metabolic modelling}, series = {Cellular and molecular life sciences : CMLS}, volume = {78}, journal = {Cellular and molecular life sciences : CMLS}, number = {12}, publisher = {Springer International Publishing AG}, address = {Cham}, issn = {1420-682X}, doi = {10.1007/s00018-021-03844-4}, pages = {5123 -- 5138}, year = {2021}, abstract = {Genome-scale metabolic networks for model plants and crops in combination with approaches from the constraint-based modelling framework have been used to predict metabolic traits and design metabolic engineering strategies for their manipulation. With the advances in technologies to generate large-scale genotyping data from natural diversity panels and other populations, genome-wide association and genomic selection have emerged as statistical approaches to determine genetic variants associated with and predictive of traits. Here, we review recent advances in constraint-based approaches that integrate genetic variants in genome-scale metabolic models to characterize their effects on reaction fluxes. Since some of these approaches have been applied in organisms other than plants, we provide a critical assessment of their applicability particularly in crops. In addition, we further dissect the inferred effects of genetic variants with respect to reaction rate constants, abundances of enzymes, and concentrations of metabolites, as main determinants of reaction fluxes and relate them with their combined effects on complex traits, like growth. Through this systematic review, we also provide a roadmap for future research to increase the predictive power of statistical approaches by coupling them with mechanistic models of metabolism.}, language = {en} } @article{TongKuekenNikoloski2020, author = {Tong, Hao and K{\"u}ken, Anika and Nikoloski, Zoran}, title = {Integrating molecular markers into metabolic models improves genomic selection for Arabidopsis growth}, series = {Nature Communications}, volume = {11}, journal = {Nature Communications}, number = {1}, publisher = {Nature Publishing Group UK}, address = {London}, issn = {2041-1723}, doi = {10.1038/s41467-020-16279-5}, pages = {9}, year = {2020}, abstract = {The current trends of crop yield improvements are not expected to meet the projected rise in demand. Genomic selection uses molecular markers and machine learning to identify superior genotypes with improved traits, such as growth. Plant growth directly depends on rates of metabolic reactions which transform nutrients into the building blocks of biomass. Here, we predict growth of Arabidopsis thaliana accessions by employing genomic prediction of reaction rates estimated from accession-specific metabolic models. We demonstrate that, comparing to classical genomic selection on the available data sets for 67 accessions, our approach improves the prediction accuracy for growth within and across nitrogen environments by 32.6\% and 51.4\%, respectively, and from optimal nitrogen to low carbon environment by 50.4\%. Therefore, integration of molecular markers into metabolic models offers an approach to predict traits directly related to metabolism, and its usefulness in breeding can be examined by gathering matching datasets in crops. An increase in genomic selection (GS) accuracy can accelerate genetic gain by shortening the breeding cycles. Here, the authors introduce a network-based GS method that uses metabolic models and improves the prediction accuracy of Arabidopsis growth within and across environments.}, language = {en} }