Deciphering metabolic and cellular effectors of nutritional compensation in the circadian clock - Project Summary: The circadian clock is used by almost every eukaryotic organism on the planet to keep time. The 24-hour circadian period length is buffered against fluctuations in external conditions, including temperature and nutrient levels, in a ubiquitous phenomenon called compensation. The molecular mechanisms underlying period compensation are not well understood in any organism. The long-term goal of the laboratory is to elucidate the mechanisms underlying compensation, in particular nutritional compensation, and the interactions between compensation effectors and the core clock network. Work will begin in the fungal model Neurospora crassa from which much of the current knowledge in circadian biology has derived. The regulatory architecture of Neurospora’s core clock network is functionally homologous to animal clocks. Furthermore, Neurospora was the first clock model with known mutations that cause defects in nutritional compensation, where period length is no longer buffered from environmental nutrient levels. Our laboratory previously discovered that genetic perturbation of top candidate fungal/human homologous genes caused nutrient-dependent changes in the circadian period length, definitively establishing nutritional compensation in mammalian circadian clocks. The overall objective of this proposal is to investigate the most significant nutritional compensation defects identified in Neurospora for conservation with mammalian cells and for molecular mechanisms of circadian compensation. The goals of this research are: 1) to define cellular effectors and metabolic variables that control circadian oscillations in fungi and test for conservation in human cells, and 2) build gene regulatory networks from time series transcriptomics across nutrients and model eukaryotic compensation. This work will break ground into compensation mechanism, a defining feature of eukaryotic circadian clocks. It is well established that chronic jet-lag, shift work exposure, or any condition causing prolonged desynchronization between the human body clock and environmental light/dark cycles increase risk to develop cancer, cardiovascular disease, or metabolic syndrome. Taken together with the modern diet and frequent evening light exposure, it is critically important for human health and wellbeing to understand how the circadian clock is buffered from environmental conditions.
