Final Report Summary - CIRCATRANS (Control of mouse metabolism by circadian clock-coordinated mRNA translation)
Most living organisms on earth presented biological rhythms which play a fundamental role in the coordination of their physiology and behavior. The discovery of the molecular circadian clock gives important insight into the mechanisms involved in the generation of these rhythms. Indeed, this molecular clock orchestrates the rhythmic transcription of clock-controlled genes involved in different aspects of metabolism, for example lipid, carbohydrate, and xenobiotic metabolisms in the liver. However, we shown during the period of this ERC grant that the circadian clock could also exert its function through the coordination of mRNA translation. Namely, the circadian clock influences the temporal translation of a subset of mRNAs by controlling the expression and activation of translation initiation factors, as well as the clock-dependent rhythmic activation of signaling pathways involved in their regulation. These rhythmically translated mRNAs are mainly involved in ribosome biogenesis and mitochondrial activity, two key process of the cell. To evaluate the impact of this rhythmic translation on protein accumulation, we performed a quantitative proteomic analysis of the rhythmic liver proteome. Our analysis identified over five thousand proteins of which several hundred showed robust diurnal oscillations with peak phases enriched in the morning and during the night and related to core hepatic physiological functions. Combined mathematical modeling of temporal protein and mRNA profiles indicated that proteins accumulated with reduced amplitudes and significant delays, consistent with protein half-live data. Moreover, a group comprising about half of the rhythmic proteins showed no corresponding rhythmic mRNAs, indicating significant translational or post-translational diurnal control. These proteins were highly enriched in secreted proteins accumulating tightly during the night and their secretion persisted in clock deficient animals. We were able to show that this rhythmic secretion is indeed regulated by food-driven regulation of the secretion machinery through post-translational modifications. Similar analysis of hepatocytes sub-cellular compartments allow us to show a highly rhythmic accumulation of molecular complexes in the nucleus regulated at the post-translational level and regulated key functions like transcription, ribosome biogenesis, DNA repair, and cell cycle.