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How Do Environmental Stimuli Set Individual Circadian Clocks to Stochastic Phases? [O’Shea Lab]

How Do Environmental Stimuli Set Individual Circadian Clocks to Stochastic Phases? [O’Shea Lab]

Many organisms on earth have evolved an endogenous self-sustained pacemaker, called the circadian clock, to anticipate daily changes in the environment and adapt its physiology. The circadian clock is an approximately 24 h-period oscillator that can free-run in the absence of external environmental cues. It can also be­­­ entrained and synchronized with external diurnal (daily) cycles, which is achieved by resetting the phase of the clock in response to cues such as temperature or light/darkness.

It has been known since the 1970s that many circadian organisms exhibit a loss of robust circadian rhythmicity (i.e. zero amplitude) in response to certain environmental cues. A similar phenomenon has also been observed in other biological oscillators with periods that span a broad range of timescales, such as cardiac pacemaker cells and the neural respiratory system. However, because previous reports were made by measuring population-averaged overt rhythms of physiology, what is happening in individual cellular circadian clocks has remained obscure.

In the present study, we investigated the single-cell behavior and mechanisms underlying the loss of population-level oscillations using the unicellular cyanobacterium S. elongatus, which has the simplest known circadian clock. The cyanobacterial clock state can be directly monitored by a fluorescent protein reporter expressed under the control of a circadian promoter. By scanning the phase resetting responses of the clock to temperature changes, we found that population-level arrhythmicity occurs when critical temperature changes applied at particular initial phases elicit desynchronized, stochastic phases in the oscillations of individual cells. With an experimentally constrained mathematical model, we quantitatively explained the induction of stochastic phases in terms of the dynamical properties of the clock as an oscillatory system, and explored the physiological relevance of the properties for accurately-timed rhythmicity in changing environmental conditions.

Our work elucidates the long-standing phenomenon of the population-averaged, organismal-level arrhythmicity that is conserved in many circadian systems, and presents a systematic approach to study oscillations, a prevalent and significant dynamical phenomenon in biology. Future investigations are needed to relate the dynamical properties to the underlying molecular composition of the cyanobacterial circadian clock, and to build upon the general insights gained into individual cellular clocks to study multicellular circadian systems.

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by Siting Gan and Erin O’Shea

Siting Gan

Siting Gan