Circadian Clock Project
Circadian Clock and Lifespan/Aging Timer Project
Research Summary
background
Many organisms exhibit circadian rhythms, which are governed by a circadian clock. Clock genes and their encoded proteins form transcriptional/ translational feedback loops (TTFLs) that drive gene expression rhythms. Disruption of the circadian clock increases the risk of developing many diseases including insomnia, hypertension, metabolic disorders, and cancers.
objective 1. circadian quartz
How does the circadian clock autonomously oscillate with a period of about 24 hours? While the canonical TTFL model shown below is an essential component of the clock that regulates expression of downstream circadian genes, we believe that the critical timekeeping aspect of the clock is maintained by protein dynamics, where protein modifications and protein conformational changes regulate protein-protein interactions in an oscillatory manner. Thus, TTFL is required for clock read-out and is akin to the hands of the clock, while protein dynamics may be more similar to the quartz timekeeper in the clock. Currently we are studying TTFL-independent protein-based clock components to identify the quartz timing mechanism.
objective 2. clock aging
Disruption of the circadian clock causes dysregulation of gene expression rhythms. This leads to functional declines including aging-associated declines, which we refer to as “clock aging”. We are studying the molecular mechanisms of how aging disrupts the functional rhythms of the circadian clock and how clock perturbations cause aging-associated symptoms.
Selected Publications
- Abe et al., (2022) Rhythmic transcription of Bmal1 stabilizes the circadian timekeeping system in mammals. Nature Communications, 13 (1): 4652.
- Yoshitane et al., (2022) mTOR-AKT signaling in cellular clock resetting triggered by osmotic stress. Antioxidants & Redox Signaling, 37(10):631.
- Hiroki et al., (2022) Molecular encoding and synaptic decoding of context during salt chemotaxis in C. elegans. Nature Communications, 13(1): 2928.
- Masuda et al., (2020) “Mutation of a PER2 phosphodegron perturbs the circadian phosphoswitch.” Proc. Natl. Acad. Sci. USA, 117(20): 10888-10896.
- Yoshitane et al., (2019) “Functional D-box sequences reset the circadian clock and drive mRNA rhythms.” Communications Biology, 2: 300.
- Imamura et al., (2018) “ASK family kinases mediate cellular stress and redox signaling to circadian clock.” Proc. Natl. Acad. Sci. USA, 115(14): 3646-3651.
- Terajima et al., (2017) “ADARB1 catalyzes circadian A-to-I editing and regulates RNA rhythm.” Nature Genetics, 49(1): 146-151.