Non-transcriptional mechanisms of the human circadian clock. (360G-Wellcome-093734_Z_10_Z)

Circadian (or daily) rhythms permeate biology. They are manifest at all levels of biological scale from social activity to cognitive ability - from physiology to self-sustained rhythms in cellular gene expression. It is well established that disruption of our biological clock correlates with impaired performance and increased likelihood of diseased states e.g. metabolic syndrome and obesity. Understanding the intrinsic cellular clock mechanism therefore constitutes an important goal for treatin g human disease as well as increasing workforce productivity. The consensus model for cellular time-keeping posits several inter-linked transcriptional-translational feedback loops at their mechanistic heart. However we have recently observed that human erythrocytes, which lack the capacity for gene expression, exhibit robust rhythms in post-translational modifications associated with cellular redox metabolism. We have also shown this is conserved in murine tissues and algae, and therefore li kely represents an evolutionarily ancient eukaryotic clock mechanism. If funded, this work will likely produce a paradigm shift for many aspects of cell biology with important consequences for understanding the temporal regulation of physiology at a deeper level..