When it's dark, and we start to fall asleep, most of us think we're tired because our bodies need rest. Yet circadian rhythms affect our bodies not just on a global scale, but at the level of individual organs, and even genes.
Now, scientists at the Salk Institute have determined the specific genetic switches that sync liver activity to the circadian cycle. Their finding gives further insight into the mechanisms behind health-threatening conditions such as high blood sugar and high cholesterol.
"We know that genes in the liver turn on and off at different times of day and they're involved in metabolizing substances such as fat and cholesterol," says Satchidananda Panda, co-corresponding author on the paper and associate professor in Salk's Regulatory Biology Laboratory. "To understand what turns those genes on or off, we had to find the switches."
To their surprise, they discovered that among those switches was chromatin, the protein complex that tightly packages DNA in the cell nucleus. While chromatin is well known for the role it plays in controlling genes, it was not previously suspected of being affected by circadian cycles.
Panda and his colleagues, including Joseph R. Eckercircadian cycles, holder of the Salk International Council Chair in Genetics, report their results December 5 in Cell Metabolism.
Over the last ten years, scientists have begun to discover more about the relationship between circadian cycles and metabolism. Circadian cycles affect nearly every living organism, including plants, bacteria, insects and human beings.
"It's been known since the early eighteenth century that plants kept in darkness still open their leaves in 24 hour cycles. Similarly, human volunteers also maintain circadian rhythms in dark rooms. Now we're determining the regulatory processes that control those responses," says Ecker, who was recently elected a fellow of the American Association for the Advancement of Science for his work on the genetics of plant and human cells.
Panda offers an example of human circadian influenced behavior that is painfully familiar to all parents of newborns: Why do infants wake up in the middle of the night? It isn't because they aren't yet "trained" to a regular schedule, but because their internal circadian clocks haven't even developed.
"Once the clock is developed, the infant can naturally sleep through the night," Panda says. "On the other end of the scale, older people with dementia have sleep problems because their biological clock has degenerated."
In the case of humans and other vertebrates, a brain structure called the suprachiasmatic nucleus controls circadian responses. But there are also clocks throughout the body, including our visceral organs, that tell specific genes when to make the workhorse proteins that enable basic functions in our bodies, such as producing glucose for energy.
In the liver, genes that control the metabolism of fat and cholesterol turn on and off in sync with these clocks. But genes do not switch on and off by themselves. Their activity is regulated by the "epigenome," a set of molecules that signal to the genes how many proteins they should make, and, most importantly from the circadian point of view, when they should be made.
"We know that when we eat determines when a particular gene turns on or off, for example, if we eat only at nighttime, a gene that should be turned on during the day will turn on at night," Panda says.
For this reason, the epigenome is of particular interest for health, since we can control when we eat. An earlier study from Panda's lab, published last May in Cell Metabolism, suggested that we should observe a 16-hour fast between our evening and morning meals.
"In response to natural cycles, our body has evolved to make glucose at nighttime," Panda says. "But if on top of that you eat, you're creating excess glucose and that damages organs, which leads to diabetes. It's like over-charging a car battery. Bad things will happen."
In short, while we can't control what genes we're born with, we do have some influence over what they do. Nevertheless, the interplay between genome and epigenome is extremely complex. Panda, Ecker and their colleagues, including the paper's co-first authors Salk postdoctoral researchers, Christopher Vollmers and Robert J. Schmitz, did their studies in mice. In the mouse liver, they discovered more than 3,000 epigenomic elements, which regulate the circadian cycles of 14,492 genes. Comparing the mouse genome to the human genome, they find many of the same genes.
"Now that we know where the switches are, it brings us one step closer to understanding the mechanism of gene regulation," says Panda, "For example, it helps us restrict our search for other factors to particular regions of the genome. In other words, at least we now know to search in Alaska, rather than Australia. But Alaska's still a big place."
Other researchers on the study were: Jason Nathanson and Gene Yeo, of the University of California, San Diego
The work was supported by the Blasker Science and Technology Grant Award from the San Diego Foundation; the National Institutes of Health; the Mary K. Chapman Foundation; the Howard Hughes Medical Institute; the Gordon and Betty Moore Foundation; and the Pew Scholars Program in Biomedical Sciences.
About the Salk Institute for Biological Studies:
The Salk Institute for Biological Studies is one of the world's preeminent basic research institutions, where internationally renowned faculty probe fundamental life science questions in a unique, collaborative, and creative environment. Focused both on discovery and on mentoring future generations of researchers, Salk scientists make groundbreaking contributions to our understanding of cancer, aging, Alzheimer's, diabetes and infectious diseases by studying neuroscience, genetics, cell and plant biology, and related disciplines.
Faculty achievements have been recognized with numerous honors, including Nobel Prizes and memberships in the National Academy of Sciences. Founded in 1960 by polio vaccine pioneer Jonas Salk, M.D., the Institute is an independent nonprofit organization and architectural landmark.
Andy Hoang | Source: Newswise
Further information: www.salk.edu
Further Reports about: Biological Studies > Biomedical Science > cell death > Cell Metabolism > circadian rhythm > cycles > epigenetic > genetic switch > human cell > liver > metabolism > Nobel Prize > specific gene > Switches
More articles from Life Sciences:
Epidemic of Escherichia coli infections traced to 1 strain of bacteria
17.12.2013 | George Washington University School of Public Health and Health Services
MRSA strain gained dominance with help from skin bacteria
17.12.2013 | American Society for Microbiology
A 12-year study of massive stars has reaffirmed that our Galaxy has four spiral arms, following years of debate sparked by images taken by NASA's Spitzer Space Telescope that only showed two arms.
The new research, which is published online today [17 December] in the Monthly Notices of the Royal Astronomical Society, is part of the RMS Survey, which was launched by academics at the University of Leeds.
Astronomers cannot see what our Galaxy, which is called the Milky Way, looks like because we ...
In collaboration with the University of Basel, an international team of researchers has observed a strong energy loss caused by frictional effects in the vicinity of charge density waves.
This may have practical significance in the control of nanoscale friction. The results have been published in the scientific journal Nature Materials.
Friction is often seen as an adverse phenomenon that leads to wear and causes energy loss. Conversely, however, too little friction can be a disadvantage as well – ...
A new type of transistor that could make possible fast and low-power computing devices for energy-constrained applications such as smart sensor networks, implantable medical electronics and ultra-mobile computing is feasible, according to Penn State researchers.
Called a near broken-gap tunnel field effect transistor (TFET), the new device uses the quantum mechanical tunneling of electrons through an ultrathin energy barrier to provide high current at low voltage.
Penn State, the National Institute of Standards and Technology and IQE, a specialty wafer manufacturer, jointly presented their findings at ...
The team of Johannes Zuber at the IMP in Vienna, Austria, managed to overcome remaining key limitations of RNA interference (RNAi) - a unique method to specifically shut off genes.
By using an optimized design, the scientists were able to inhibit genes with greatly enhanced efficiency and accuracy. The new method facilitates the search for drug targets and improves the interpretation of experimental results.
The IMP will make this „RNAi toolkit“ available to researchers. Results of the study are published in ...
Research The dangerous parasite Schistosoma mansoni that causes snail fever in humans could become significantly less common in the future a new international study led by researchers from the University of Copenhagen predicts.
The results are surprising because they contradict the general assumption that climate change leads to greater geographical spread of diseases. The explanation is that the parasite’s host snails stand to lose suitable habitat due to climate change.
“Our research shows that the expected effects of climate change will lead ...
17.12.2013 | Health and Medicine
17.12.2013 | Health and Medicine
17.12.2013 | Transportation and Logistics
11.12.2013 | Event News
10.12.2013 | Event News
05.12.2013 | Event News