March 14, 2007 — A study in Switzerland uses
the tools of physics to show how our circadian clocks manage to keep
accurate time in the noisy cellular environment.
In an article appearing in the journal Molecular Systems Biology,
researchers from the Ecole Polytechnique Federale de Lausanne
demonstrate that the stability of cellular oscillators depends on
specific biochemical processes, reflecting recent association studies
in families affected by advanced sleep phase syndrome.
Circadian rhythms are cyclical changes in physiology, gene
expression, and behavior that run on a cycle of approximately one day,
even in conditions of constant light or darkness. Peripheral organs in
the body have their own cellular clocks that are reset on a daily basis
by a central master clock in the brain. The operation of the cellular
clocks is controlled by the coordinated action of a limited number of
core clock genes.
The oscillators work like this: the cell receives a signal from the
master pacemaker in the hypothalamus, and then these clock genes
respond by setting up concentration gradients that change in a periodic
manner. The cell "interprets" these gradients and unleashes
tissue-specific circadian responses. Some examples of output from these
clocks are the daily rhythmic changes in body temperature, blood
pressure, heart rate, concentrations of melatonin and glucocorticoids,
urine production, acid secretion in the gastrointestinal tract, and
changes in liver metabolism.
In the tiny volume of the cell, however, the chemical environment is
constantly fluctuating. How is it possible for all these
cell-autonomous clocks to sustain accurate 24-hour rhythms in such a
Using mouse fibroblast circadian bioluminescence recordings from the
Schibler Lab at the University of Geneva, the researchers turned to
dynamical systems theory and developed a mathematical model that
identified the molecular parameters responsible for the stability of
the cellular clocks. Stability is a measure of how fast the system
reverts to its initial state after being perturbed.
"To my knowledge we are the first to discuss how the stability of
the oscillator directly affects bioluminescence recordings," explains
Felix Naef, a systems biology professor at EPFL and the Swiss Institute
for Experimental Cancer Research. "We found that the phosphorylation
and transcription rates of a specific gene are key determinants of the
stability of our internal body clocks."
This result is consistent with recent research from the University
of California, San Francisco involving families whose circadian clocks
don’t tick quite right. These families’ clocks are shorter than 24
hours, and they also have mutations in oscillator-related genes. The
current results shed light on how a genetically-linked phosphorylation
event gone wrong could lead to inaccurate timing of our body clockworks.
Soource : Ecole Polytechnique Fédérale de Lausanne