Posts tagged BMAL1
Articles and news from the latest research reports.
Chrono, the last piece of the circadian clock puzzle?
In an article published today in PLOS Biology, researchers from the RIKEN Brain Science Institute in Japan report the identification of Chrono, a gene involved in the regulation of the body clock in mammals and that might be a key component of the body’s response to stress.
All organisms, from mammals to fungi, have daily cycles controlled by a tightly regulated internal clock, called the circadian clock. The whole-body circadian clock, influenced by the exposure to light, dictates the wake-sleep cycle. At the cellular level, the clock is controlled by a complex network of genes and proteins that switch each other on and off based on cues from their environment.
Most genes involved in the regulation of the circadian clock have been characterized, but Akihiro Goriki, Toru Takumi and their colleagues from RIKEN and Hiroshima University in Japan and University of Michigan in the United States knew that a key component was missing and sough to uncover it in mammals.
In the study, the team performed a genome-wide chromatin immunoprecipitation analysis for genes that were the target of BMAL1, a core clock component that binds to many other clock genes, regulating their transcription.
The authors characterize a new circadian gene that they name Chrono. They show that CHRONO functions as a transcriptional repressor of the negative feedback loop in the mammalian clock: the protein CHRONO binds to the regulatory region of clock genes, with its repressor function oscillating in a circadian manner. The expression of core clock genes is altered in mice lacking the Chrono gene, and the mice have longer circadian cycles.
"These results suggest that Chrono functions as a core clock repressor,” conclude the authors.
In addition, they demonstrate that the repression mechanism of Chrono is under epigenetic control and links, via a glucocorticoid receptor, to metabolic pathways triggered by behavioral stress.
These findings are confirmed by another study by the University of Pennsylvania, also published in PLOS Biology today. In the study, John Hogenesch and his team prove the existence of Chrono using a computer-based analysis.
Broken cellular ‘clock’ linked to brain damage
A new discovery may help explain the surprisingly strong connections between sleep problems and neurodegenerative conditions such as Alzheimer’s disease. Sleep loss increases the risk of Alzheimer’s disease, and disrupted sleeping patterns are among the first signs of this devastating disorder.
Scientists at Washington University School of Medicine in St. Louis and the University of Pennsylvania have shown that brain cell damage similar to that seen in Alzheimer’s disease and other disorders results when a gene that controls the sleep-wake cycle and other bodily rhythms is disabled.
The researchers found evidence that disabling a circadian clock gene that controls the daily rhythms of many bodily processes blocks a part of the brain’s housekeeping cycle that neutralizes dangerous chemicals known as free radicals.
“Normally in the hours leading up to midday, the brain increases its production of certain antioxidant enzymes, which help clean up free radicals,” said first author Erik Musiek, MD, PhD, assistant professor of neurology at the School of Medicine. “When clock genes are disabled, though, this surge no longer occurs, and the free radicals may linger in the brain and cause more damage.”
Musiek conducted the research in the labs of Garret FitzGerald, MD, chairman of pharmacology at the University of Pennsylvania, and of David Holtzman, MD, the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology at Washington University School of Medicine, who are co-senior authors.
The study appears Nov. 25 in The Journal of Clinical Investigation.
Musiek studied mice lacking a master clock gene called Bmal1. Without this gene, activities that normally occur at particular times of day are disrupted.
“For example, mice normally are active at night and asleep during the day, but when Bmal1 is missing, they sleep equally in the day and in the night, with no circadian rhythm,” Musiek said. “They get the same amount of sleep, but it’s spread over the whole day. Rhythms in the way genes are expressed are lost.”
FitzGerald uses mice lacking Bmal1 to study whether clock cells have links to diabetes and heart disease. He has shown that clock genes influence blood pressure, blood sugar and lipid levels.
Several years ago, Musiek, who at the time was a neurology resident at the University of Pennsylvania, and FitzGerald decided to investigate how knocking out Bmal1 affects the brain. Holtzman, who has published pioneering work on sleep and Alzheimer’s disease, encouraged Musiek to continue and expand these studies when he came to Washington University as a postdoctoral fellow.
In the new study, Musiek found that as the mice aged, many of their brain cells became damaged and did not function normally. The patterns of damage were similar to those seen in Alzheimer’s disease and other neurodegenerative disorders.
“Brain cell injury in these mice far exceeded that normally seen in aging mice,” Musiek said. “Many of the injuries appear to be caused by free radicals, which are byproducts of metabolism. If free radicals come into contact with brain cells or other tissue, they can cause damaging chemical reactions.”
This led Musiek to examine the production of key antioxidant enzymes, which usually neutralize and help clear free radicals from the brain, thereby limiting damage. He found levels of several antioxidant proteins peak in the middle of the day in healthy mice. However, this surge is absent in mice lacking Bmal1. Without the surge, free radicals may remain in the brain longer, contributing to the damage Musiek observed.
“We’re trying to identify more specifics about how problems in clock genes contribute to neurodegeneration, both with and without influencing sleep,” Musiek said. “That’s a challenging distinction to make, but it needs to be made because clock genes appear to control many other functions in the brain in addition to sleeping and waking.”
(Source: news.wustl.edu)