Circadian rhythms are daily oscillations in behavior with a nearly 24-hour period that are generated by an internal biological clock. Across many organisms, health and fitness are impaired when the circadian clock does not appropriately synchronize with the daily cycles in the external environment. However, the mechanisms underlying these health costs are not clear. We are pursuing the hypothesis that a key function of the circadian clock is to optimize metabolism in anticipation of predicted changes in the environment. We are combining biophysical and biochemical measurements with experimentally-driven mathematically modeling in the bacterial model organism Synechococcus elongatus to study the interlocking relationships between clocks, metabolism, and organismal fitness. In this organism, the relationship between the clock and metabolism is very direct, and the core circadian oscillator can be reconstituted in a test tube using purified protein, making this an exceptionally power system to study this hypothesis.
In Aim 1, we will determine the molecular mechanisms that maintain robust rhythms in the presence of metabolic signals in vitro using purified proteins.
In Aim 2, we will determine the metabolic effects of clock mutants in vivo and their role in a metabolic feedback loop coupling clock output to input.
In Aim 3, we will determine the impact of misalignment between the clock and metabolism on the reproductive rate and capacity of single cells in order to link these findings to organismal fitness.
Many organisms, including humans, have internal biological clocks that synchronize behavioral rhythms with the 24-hour rhythms in the environment. When these so-called circadian clocks fail to maintain appropriate rhythms, as in jet lag or shift work, the result can include impaired health, metabolic disruption, and decreased lifespan. We are studying bacteria that have the simplest known circadian clock with the goal of building mathematical models describing how the molecular components work together to generate rhythms and how these rhythms are coupled to metabolism and fitness.
|Chew, Justin; Leypunskiy, Eugene; Lin, Jenny et al. (2018) High protein copy number is required to suppress stochasticity in the cyanobacterial circadian clock. Nat Commun 9:3004|
|Pittayakanchit, Weerapat; Lu, Zhiyue; Chew, Justin et al. (2018) Biophysical clocks face a trade-off between internal and external noise resistance. Elife 7:|
|Hong, Lu; Vani, Bodhi P; Thiede, Erik H et al. (2018) Molecular dynamics simulations of nucleotide release from the circadian clock protein KaiC reveal atomic-resolution functional insights. Proc Natl Acad Sci U S A 115:E11475-E11484|
|Leypunskiy, Eugene; K?c?man, Emre; Shah, Mili et al. (2018) Geographically Resolved Rhythms in Twitter Use Reveal Social Pressures on Daily Activity Patterns. Curr Biol 28:3763-3775.e5|
|Leypunskiy, Eugene; Lin, Jenny; Yoo, Haneul et al. (2017) The cyanobacterial circadian clock follows midday in vivo and in vitro. Elife 6:|
|Lambert, Guillaume; Chew, Justin; Rust, Michael J (2016) Costs of Clock-Environment Misalignment in Individual Cyanobacterial Cells. Biophys J 111:883-891|
|Chang, Yong-Gang; Cohen, Susan E; Phong, Connie et al. (2015) Circadian rhythms. A protein fold switch joins the circadian oscillator to clock output in cyanobacteria. Science 349:324-8|
|Pattanayak, Gopal K; Lambert, Guillaume; Bernat, Kevin et al. (2015) Controlling the Cyanobacterial Clock by Synthetically Rewiring Metabolism. Cell Rep 13:2362-2367|
|Lin, Jenny; Chew, Justin; Chockanathan, Udaysankar et al. (2014) Mixtures of opposing phosphorylations within hexamers precisely time feedback in the cyanobacterial circadian clock. Proc Natl Acad Sci U S A 111:E3937-45|
|Pattanayak, Gopal K; Phong, Connie; Rust, Michael J (2014) Rhythms in energy storage control the ability of the cyanobacterial circadian clock to reset. Curr Biol 24:1934-8|
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