Multiscale Problems in Circadian Systems Biology: From Gene to Cell to Performance.

摘要

The circadian system or 'biological clock' orchestrates the temporal organization of several physiological and metabolic processes over a 24-hour period in most living organisms. In mammals, the circadian timing system has a hierarchical organization composed of the central pacemaker in the suprachiasmatic nucleus (SCN) which coordinates the oscillating activity of peripheral clocks that are present in almost all tissues. At the molecular level, circadian oscillations in both SCN and peripheral cells are based on negative autoregulation of gene expression involving essentially the same core clock components. At the tissue level, the SCN consists of a coupled network of heterogeneous neurons that fire synchronously through neurotransmitter coupling and are entrained to 24-hour period through daily light-dark cycles. At the organismal level, the SCN synchronizes peripheral tissue clocks via hormonal and indirect cues such as feeding time, probably through modifications of metabolite availability. More recently, experiments have shown that interactions between circadian and metabolic systems are bidirectional in that metabolites can feedback into the clock. These findings emphasize the need of a multiscale integrative approach to understanding circadian regulatory processes. Here, we adopt a quantitative systems biology approach that uncovers critical properties of the circadian oscillator at various scales (neurons, SCN, periphery).