Metabolite accumulation mediates the shift between HOC and LOC phases in the Yeast Metabolic Cycle

The Yeast Metabolic Cycle (YMC) is a molecular system that serves as a model to study the internal clock that maintains homeostasis in complex organisms. Traditionally, this ultradian rhythm has been studied in the three phases where mature mRNA transcripts show peak accumulation. However, recent studies have shown that the YMC can be interpreted as a two-phase cycle based on altered redox states, known as the high (HOC) and low oxygen consumption (LOC) phases. The length of the HOC phase is fixed and its frequency is nutrient dependent but the nature of the HOC to LOC transition is poorly defined. Here, we use multivariate statistics to integrate metabolic, chromatin and transcriptional changes across the YMC to study the levels of organization that connect them. Our model reveals that both the HOC-LOC and LOC-HOC phase transitions in the YMC are coordinated by accumulating metabolites, reflecting cellular energetics and redox state. We propose that the cycling behavior of chromatin states, transcription and transcripts is a consequence of accumulating metabolites at phase transitions, which function by modulating protein activity and coordinating biochemical pathways to maintain cellular homeostasis.