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

Abstract

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 (378C) and lowered (108C) temperatures relative to optimal reference conditions (288C) 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.

Cold Temperature Induces the Reprogramming of Proteolytic Pathways in Yeast

“…Budding yeast tolerate changes in temperature by stress response programs at multiple levels that include metabolic, transcriptional, and degradation pathways. Low temperature promotes a decrease in the transcription levels of multiple genes involved in plasma membrane transport as well as a specific metabolic response (46,47). We propose that, in the same way, proteolytic systems tune their roles to produce the appropriate protein homeostasis response at low temperature.…”

Dynamic Transcriptional and Metabolic Responses in Yeast Adapting to Temperature Stress

“…The generated dataset forms an ideal basis for applying more advanced analysis methods such as time-lagged correlation or Granger causality (Granger, 1980) to infer potential causal relationships between metabolites and transcripts as well as to discern the temporal dynamics of temperature stress response as described in the accompanying article (Walther, 2010).…”

Deciphering Herbivory-Induced Gene-to-Metabolite Dynamics in Nicotiana attenuata Tissues Using a Multifactorial Approach

“…The patterns of correlation between metabolite and transcript data have been successfully analyzed in a few studies using highresolution time-course analyses (Hirai et al, 2004), but most studies in this field, including our work (Fig. 7), have reported significant differences in the temporal dynamics of transcriptomes and metabolomes (Walther et al, 2010;Takahashi et al, 2011). Considering the complex interdependencies between metabolites and transcripts, we sought to detect and interpret genemetabolite interactions at the level of isolated pathways for TvS comparisons using the interactive responses of genes and metabolites as associative metrics and used this approach to study previously reviewed oxylipin and 17-HGL-DTG pathways.…”