Research Overview

When the budding yeast Saccharomyces cerevisiae is grown to a high density (resembling a colony) and then continuously fed low concentrations of glucose (using a chemostat), the cell population exhibits robust oscillations in oxygen consumption, which we term yeast metabolic cycles (YMC). These cycles are ~4-5 hours in length and consist of phases of rapid oxygen consumption (oxidative) that alternate with phases of minimal oxygen consumption (reductive). Remarkably, over half of the yeast genome is expressed periodically as a precise function of the YMC. Gene products with functions associated with energy and metabolism and those localized to the mitochondria tend to be expressed periodically. Moreover, genes that encode proteins with a common function tend to display similar temporal expression profiles.

Analysis of the YMC expression dataset revealed three superclusters of gene expression, which defined three major phases of the YMC: OX (oxidative, respiratory), RB (reductive, building), and RC (reductive, charging). Different categories of genes peak during each phase, and cells traverse each of these three phases in every cycle. The extensive orchestration of gene expression around bursts of respiration during the YMC indicates that many essential cellular and metabolic processes (e.g., respiration, mitochondria biogenesis, ribosome biogenesis, cell division, fatty acid oxidation, autophagy) are compartmentalized in time. Temporal compartmentalization might enable cells to execute a variety of processes in a more coordinated and efficient fashion and help minimize futile reactions.

The many oscillating gene expression patterns predict that the YMC should differentially control metabolic state as a function of these respiratory oscillations. Certain metabolites might exhibit periodic fluctuation and, in turn, play a reciprocal role in regulating the YMC. We developed comprehensive metabolite profiling methods to monitor the intracellular concentrations of over ~150 common metabolites at different time points during the YMC. The results of these surveys show that many metabolites including amino acids, nucleotides, and carbohydrates, oscillate in abundance with a periodicity precisely matching that of the YMC. Thus, cyclic changes in metabolic state occur during the life of a cell.

Henceforth, the YMC microarray and metabolite data sets together provide a unique overview of the gene expression and metabolic programs that occur during the life of a eukaryotic cell, from which many sound biological predictions can be formulated and tested. As discussed above, oscillations of key metabolites will almost certainly be important for the temporal regulation of fundamental cellular processes and the establishment of a metabolic cycle. By using the chemostat to synchronize yeast cells and allowing them to proceed through this continuous, slow-growth state, we can observe aspects of the life of a yeast cell that would otherwise be very difficult. How the numerous periodic gene expression patterns are specified with such precision, and the mechanisms by which fundamental processes such as cell division and mitochondria homeostasis are coupled to metabolic cues remain important open questions.

The YMC might also serve as a paradigm for understanding the underlying basis of other biological cycles, such as the circadian, hibernation, and sleep-wake cycles. Temporal compartmentalization of numerous processes - most notably of highly metabolically active states (e.g., wakefulness during sleep-wake, interbout arousals during hibernation), is also intrinsic to these other cycles. As a result, cyclic changes in metabolic state might be a fundamental driving force for some of these biological cycles.

Research Interests
  • Metabolic and biological cycles
  • Mechanisms of cell growth control
  • Coordination of fundamental cellular processes with metabolic or redox state
  • Redox biology
  • Oxidative stress, nutritional stress
  • Bioinformatic analysis of temporal gene expression and metabolite profiling data

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