Watching the Wheels Turn on the Biological Clock
Our master circadian clock resides in a small group of about 10'000 neurons in the brain, called the suprachiasmatic nucleus. However, similar clocks are ticking in nearly all cells of the body
A system to study gene regulation live in single cells
The lab of Ueli Schibler, professor at the Department of Molecular Biology of the University of Geneva, Switzerland, has demonstrated how the molecular mechanisms of circadian clocks can be studied in cultured cells.
"Given the important role of the DBP protein
in the regulation of detoxifying enzymes,
we studied the molecular mechanisms
underlying rhythmic transcription of the DBP gene,"
points out Schibler, a member of the
NCCR Frontiers in Genetics.
His team devised an elegant method to watch
under the microscope how the clock's molecular
"cogwheels" govern the rhythms of the DBP
gene in individual living cells.
The scientists engineered a cell line with a piece
of chromosome made up of only repeated DBP
gene copies and found that the daily transcription
of DBP is due to the rhythmic association of the
transcription factor BMAL1.
"This is the first time a transcription factor binding to a circadian gene could be visualized in real time in single cells" explains Markus Stratmann, first author of the article appearing in Science magazine.
The clock transcription factor must be sacrificed
To their surprise, they also found that the clock protein BMAL1 is destroyed while stimulating the expression of the DBP gene. By applying a variety of sophisticated imaging and biochemical techniques, they found that the BMAL1 molecules bound to the DBP gene are degraded by an intracellular protein destruction machine, known as the proteasome.
Curiously, chopping off the triggering protein BMAL1
is absolutely required for activating the DBP gene.
In other words, BMAL1 must die while inducing
the DBP gene to do its job.
"In a sense, these transcription factors have the same cruel fate as males of the carnivorous Praying Mantis insect. Sadly, Mantis females decapitate and begin eating their partners before the love act is even completed" says Markus Stratmann.
At the moment, the biologists can only speculate about the broader impact of their findings. "We do not yet understand why the BMAL1 protein is destroyed in order for the optimal functioning of the DBP gene to begin" remarks Ueli Schibler.
In fact, BMAL1 molecules regulate the daily activity
of many genes without getting killed while doing their
work. However, researchers noticed that genes whose
activity is not associated with the destruction of
BMAL1 are expressed many hours
later than the DBP gene.
The work helps explain the enigma of why one
transcription factor, BMAL1, can impose
dramatically different daily cycles of
gene expression to many genes.
Original article: http://www.eurekalert.org/pub_releases/2012-10/udg-wtc102312.php