Project description:We report the interdependance of PERIOD and H2A.Z to orchestrated the circadian negative feedback. H2A.Z is required for the circadian rhythm, it allows the binding of Bmal1 and PERIOD2 to the chromatin. And reciprocally, PERIOD2 aid H2A.Z deposition by interacting with the specific chaperone YL1.
Project description:We report the interdependance of PERIOD and H2A.Z to orchestrated the circadian negative feedback. H2A.Z is required for the circadian rhythm, it allows the binding of Bmal1 and PERIOD2 to the chromatin. And reciprocally, PERIOD2 aid H2A.Z deposition by interacting with the specific chaperone YL1.
Project description:We report the interdependance of PERIOD and H2A.Z to orchestrated the circadian negative feedback. H2A.Z is required for the circadian rhythm, it allows the binding of Bmal1 and PERIOD2 to the chromatin. And reciprocally, PERIOD2 aid H2A.Z deposition by interacting with the specific chaperone YL1.
Project description:The mechanistic interconnectivity between circadian regulation and the genotoxic stress response remains poorly understood. Here we show that the expression of Period 2 (Per2), a circadian regulator, is directly regulated by p53 binding to a response element in the Per2 promoter. This p53 response element is evolutionarily conserved and overlaps with the E-Box element critical for BMAL1/CLOCK binding and its transcriptional activation of Per2 expression. Our studies reveal that p53 blocks BMAL1/CLOCK binding to the Per2 promoter, leading to repression of Per2 expression. In the suprachiasmatic nucleus (SCN), p53 expression and its binding to the Per2 promoter are under circadian control. Per2 expression in the SCN is altered by p53 deficiency or stabilization of p53 by Nutlin-3. Behaviourally, p53?/? mice have a shorter period length that lacks stability, and they exhibit impaired photo-entrainment to a light pulse under a free-running state. Our studies demonstrate that p53 modulates mouse circadian behaviour.
Project description:Processes that repeat in time, such as the cell cycle, the circadian rhythm, and seasonal variations, are prevalent in biology. Mathematical models can represent our knowledge of the underlying mechanisms, and numerical methods can then facilitate analysis, which forms the foundation for a more integrated understanding as well as for design and intervention. Here, the intracellular molecular network responsible for the mammalian circadian clock system was studied. A new formulation of detailed sensitivity analysis is introduced and applied to elucidate the influence of individual rate processes, represented through their parameters, on network functional characteristics. One of four negative feedback loops in the model, the Per2 loop, was uniquely identified as most responsible for setting the period of oscillation; none of the other feedback loops were found to play as substantial a role. The analysis further suggested that the activity of the kinases CK1delta and CK1varepsilon were well placed within the network such that they could be instrumental in implementing short-term adjustments to the period in the circadian clock system. The numerical results reported here are supported by previously published experimental data.
Project description:The eukaryotic circadian oscillators consist of autoregulatory negative feedback loops. However, little is known about the role of posttranscriptional regulation of RNA in circadian oscillators. In the Neurospora circadian negative feedback loop, FRQ and FRH form the FFC complex that represses frq transcription. Here, we show that FFC also binds frq RNA and interacts with the exosome to regulate frq RNA decay. Consequently, frq RNA is robustly rhythmic as it is more stable when FRQ levels are low. Silencing of RRP44, the catalytic subunit of the exosome, elevates frq RNA levels and impairs clock function. In addition, rrp44 is a clock-controlled gene and a direct target of the WHITE COLLAR complex, and RRP44 controls the circadian expression of some ccgs. Taken together, these results suggest that FFC and the exosome are part of a posttranscriptional negative feedback loop that regulates frq transcript levels and the circadian output pathway.
