Metabolic Pathway Relationships Revealed by an Integrative Analysis of the Transcriptional and Metabolic Temperature Stress-Response Dynamics in Yeast

The integrated analysis of omics datasets covering different levels of molecular organization has become a central task of systems biology. We investigated the transcriptional and metabolic response of yeast exposed to increased (37 degrees C) and lowered (10 degrees C) temperatures relative to optimal reference conditions (28 degrees C) in the context of known metabolic pathways. Pairwise metabolite correlation levels were found to carry more pathway-related information and to extend to farther distances within the metabolic pathway network than associated transcript level correlations. Metabolites were detected to correlate stronger to their cognate transcripts (metabolite is reactant of the enzyme encoded by the transcript) than to more remote or randomly chosen transcripts reflecting their close metabolic relationship. We observed a pronounced temporal hierarchy between metabolic and transcriptional molecular responses under heat and cold stress. Changes of metabolites were most significantly correlated to transcripts encoding metabolic enzymes, when metabolites were considered leading in time-lagged correlation analyses. By applying the concept of Granger causality, we detected directed relationships between metabolites and their cognate transcripts. When interpreted as substrate-to-product directions, most of these directed Granger causality pairs agreed with the KEGG-annotated preferred reaction direction. Thus, the introduced Granger causality approach may prove useful for determining the preferred direction of metabolic reactions in cellular systems. The metabolites glutamic acid and serine were identified as central causative metabolites influencing transcript levels at later time points. Selected examples are presented illustrating the intertwined relationships between metabolites and transcripts in the yeast temperature stress adaptation process.