TY - JOUR A1 - Zakharova, A. A1 - Nikoloski, Zoran A1 - Koseska, Aneta T1 - Dimensionality reduction of bistable biological systems JF - Bulletin of mathematical biology : official journal of the Society for Mathematical Biology N2 - 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. KW - Bistability KW - Time-scales hierarchy KW - Similarity transformation KW - Canonical correlation analysis KW - Dimensionality reduction Y1 - 2013 U6 - https://doi.org/10.1007/s11538-013-9807-8 SN - 0092-8240 VL - 75 IS - 3 SP - 373 EP - 392 PB - Springer CY - New York ER - TY - JOUR A1 - Winck, Flavia Vischi A1 - Arvidsson, Samuel Janne A1 - Mauricio Riano-Pachon, Diego A1 - Hempel, Sabrina A1 - Koseska, Aneta A1 - Nikoloski, Zoran A1 - Urbina Gomez, David Alejandro A1 - Rupprecht, Jens A1 - Müller-Röber, Bernd T1 - Genome-wide identification of regulatory elements and reconstruction of gene regulatory networks of the green alga chlamydomonas reinhardtii under carbon deprivation JF - PLoS one N2 - 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. Y1 - 2013 U6 - https://doi.org/10.1371/journal.pone.0079909 SN - 1932-6203 VL - 8 IS - 11 PB - PLoS CY - San Fransisco ER - TY - JOUR A1 - Hempel, Sabrina A1 - Koseska, Aneta A1 - Nikoloski, Zoran T1 - Data-driven reconstruction of directed networks JF - The European physical journal : B, Condensed matter and complex systems N2 - We investigate the properties of a recently introduced asymmetric association measure, called inner composition alignment (IOTA), aimed at inferring regulatory links (couplings). We show that the measure can be used to determine the direction of coupling, detect superfluous links, and to account for autoregulation. In addition, the measure can be extended to infer the type of regulation (positive or negative). The capabilities of IOTA to correctly infer couplings together with their directionality are compared against Kendall's rank correlation for time series of different lengths, particularly focussing on biological examples. We demonstrate that an extended version of the measure, bidirectional inner composition alignment (biIOTA), increases the accuracy of the network reconstruction for short time series. Finally, we discuss the applicability of the measure to infer couplings in chaotic systems. Y1 - 2013 U6 - https://doi.org/10.1140/epjb/e2013-31111-8 SN - 1434-6028 VL - 86 IS - 6 PB - Springer CY - New York ER -