Cells react to extracellular perturbations with complex and intertwined responses. Systematic identification of the regulatory mechanisms that control these responses is still a challenge and requires tailored analyses integrating different types of molecular data. Here we acquired time-resolved metabolomics measurements in yeast under salt and pheromone stimulation and developed a machine learning approach to explore regulatory associations between metabolism and signal transduction. Existing phosphoproteomics measurements under the same conditions and kinase-substrate regulatory interactions were used to in silico estimate the enzymatic activity of signalling kinases. Our approach identified informative associations between kinases and metabolic enzymes capable of predicting metabolic changes. We extended our analysis to two studies containing transcriptomics, phosphoproteomics and metabolomics measurements across a comprehensive panel of kinases/phosphatases knockouts and time-resolved perturbations to the nitrogen metabolism. Changes in activity of transcription factors, kinases and phosphatases were estimated in silico and these were capable of building predictive models to infer the metabolic adaptations of previously unseen conditions across different dynamic experiments. Time-resolved experiments were significantly more informative than genetic perturbations to infer metabolic adaptation. This difference may be due to the indirect nature of the associations and of general cellular states that can hinder the identification of causal relationships. This work provides a novel genome-scale integrative analysis to propose putative transcriptional and post-translational regulatory mechanisms of metabolic processes.

MOTIVATION: Simple forms of mutualism between microorganisms are widespread in nature. Nevertheless, the role played by the environmental nutrient composition in mediating cross-feeding in microbial ecosystems is still poorly understood. RESULTS: Here, we use mixed-integer bilevel linear programming to investigate the cost of sharing metabolic resources in microbial communities. The algorithm infers an optimal combination of nutrients that can selectively sustain synergistic growth for a pair of species and guarantees minimum cost of cross-fed metabolites. To test model-based predictions, we selected a pair of Escherichia coli single gene knockouts auxotrophic, respectively, for arginine and leucine: ΔargB and ΔleuB and we experimentally verified that model-predicted medium composition significantly favors mutualism. Moreover, mass spectrometry profiling of exchanged metabolites confirmed the predicted cross-fed metabolites, supporting our constraint based modeling approach as a promising tool for engineering microbial consortia. AVAILABILITY AND IMPLEMENTATION: The software is freely available as a matlab script in the Supplementary materials. CONTACT: [email protected] SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MOTIVATION: Deciphering the response of a complex biological system to an insulting event, at the gene expression level, requires adopting theoretical models that are more sophisticated than a one-to-one comparison (i.e. t-test). Here, we investigate the ability of a novel reverse engineering approach (System Response Inference) to unveil non-obvious transcriptional signatures of the system response induced by prion infection. RESULTS: To this end, we analyze previously published gene expression data, from which we extrapolate a putative full-scale model of transcriptional gene-gene dependencies in the mouse central nervous system. Then, we use this nominal model to interpret the gene expression changes caused by prion replication, aiming at selecting the genes primarily influenced by this perturbation. Our method sheds light on the mode of action of prions by identifying key transcripts that are the most likely to be responsible for the overall transcriptional rearrangement from a nominal regulatory network. As a first result of our inference, we have been able to predict known targets of prions (i.e. PrP(C)) and to unveil the potential role of previously unsuspected genes. CONTACT: [email protected] SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Prion proteins are known to misfold into a range of different aggregated forms, showing different phenotypic and pathological states. Understanding strain specificities is an important problem in the field of prion disease. Little is known about which PrP(Sc) structural properties and molecular mechanisms determine prion replication, disease progression and strain phenotype. The aim of this work is to investigate, through a mathematical model, how the structural stability of different aggregated forms can influence the kinetics of prion replication. The model-based results suggest that prion strains with different conformational stability undergoing in vivo replication are characterizable in primis by means of different rates of breakage. A further role seems to be played by the aggregation rate (i.e. the rate at which a prion fibril grows). The kinetic variability introduced in the model by these two parameters allows us to reproduce the different characteristic features of the various strains (e.g., fibrils' mean length) and is coherent with all experimental observations concerning strain-specific behavior.

BACKGROUND: In the past years devising methods for discovering gene regulatory mechanisms at a genome-wide level has become a fundamental topic in the field of systems biology. The aim is to infer gene-gene interactions in an increasingly sophisticated and reliable way through the continuous improvement of reverse engineering algorithms exploiting microarray data. MOTIVATION: This work is inspired by the several studies suggesting that coexpression is mostly related to 'static' stable binding relationships, like belonging to the same protein complex, rather than other types of interactions more of a 'causal' and transient nature (e.g. transcription factor-binding site interactions). The aim of this work is to verify if direct or conditional network inference algorithms (e.g. Pearson correlation for the former, partial Pearson correlation for the latter) are indeed useful in discerning static from causal dependencies in artificial and real gene networks (derived from Escherichia coli and Saccharomyces cerevisiae). RESULTS: Even in the regime of weak inference power we have to work in, our analysis confirms the differences in the performances of the algorithms: direct methods are more robust in detecting stable interactions, conditional ones are better for causal interactions especially in presence of combinatorial transcriptional regulation. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.