Ever wondered why you wake up in the morning ---- even when the alarm clock isn't making jarring noises? Wonder no more. Researchers at the Salk Institute for Biological Studies have identified a new component of the biological clock, a gene responsible for starting the clock from its restful state every morning.
The biological clock ramps up our metabolism early each day, initiating important physiological functions that tell our bodies that it's time to rise and shine. Discovery of this new gene and the mechanism by which it starts the clock everyday may help explain the genetic underpinnings of sleeplessness, aging and chronic illnesses, such as cancer and diabetes, and could eventually lead to new therapies for these illnesses.
"The body is essentially a collection of clocks," says Satchindananda Panda, an associate professor in Salk's Regulatory Biology Laboratory, who led the research along with Luciano DiTacchio, a post-doctoral research associate. "We roughly knew what mechanism told the clock to wind down at night, but we didn't know what activated us again in the morning. Now that we've found it, we can explore more deeply how our biological clocks malfunction as we get older and develop chronic illness."
In a report published today in the journal Science, the Salk researchers and their collaborators at McGill University and Albert Einstein College of Medicine describe how the gene KDM5A encodes a protein, JARID1a, that serves as an activation switch in the biochemical circuit that maintains our circadian rhythm.
The discovery fills in a missing link in the molecular mechanisms that control our daily wake-sleep cycle. The central player of our biological clock is a protein called PERIOD (PER). The number of PER proteins in each of our cells rises and falls every 24 hours. Our cells use the level of PER protein as an indicator of the time of the day and tell our body when to sleep or be awake.
Scientists knew that two genes, CLOCK and BMAL1, served as the key drivers for raising PER protein levels. As the level of PER protein rises during the daytime, reaching its peak around evening, it somehow puts a break on CLOCK and BMAL, thereby reducing its own level during nighttime.
Falling PER protein levels at night causes our biological systems to slow: our blood pressure drops, our heart rate slows and our mental processes wind down. But, until now, the precise nature of the nighttime brake and what let CLOCK and BMAL proteins overcome this brake to raise PER protein levels again each morning was a mystery.
In their research, which was primarily funded by Salk's Innovation Fund, Panda and his colleagues identified JARID1a, a type of enzyme, as the molecular bugle call for cells and organs to get back to work each morning. By studying the genetic mechanisms underlying circadian rhythms in human and mouse cells and in fruit flies, the researchers discovered that JARID1a was required for normal cycling, both at the cellular level and in terms of an organisms' daily behavior.
In human and mouse cells that were genetically modified to under-produce JARID1a, the PER protein did not rise to its normal peak each day. Fruit flies that were similarly genetically altered also had low levels of PER protein. The flies lost track of time: they did not know when to sleep or wake up and took frequent naps throughout the day and night.
Digging deeper into the molecular workings of the clock, Panda and his colleagues found that each morning, JARID1a reactivates CLOCK and BMAL1 by countering the action of a brake protein HDAC1. They suspect PER protein tells HDAC1 to put a brake on its own production at night. "JARID1a tells that break to ease off, which causes CLOCK and BMAL1 drivers to rev back up every morning," Panda says.To support their findings about the clock's workings, the researchers studied genetically altered mice cells and fruit flies that lacked the JARID1a gene. They inserted JARID1a into the flies' DNA, which released the HDAC brake so the flies returned to a normal cycle. They treated mouse cells with a drug that mimics JARID1a, which allowed their biological clocks to operate normally.
With age, for instance, the biological clock seems to decline, often causing older people to suffer from difficulty sleeping. There is also strong evidence that shift workers, such as nurses and emergency personnel, who work long shifts that break them out of the normal 24-hour cycle of waking and sleeping, are at much higher risk for certain diseases.
The biological clock also appears important to the development of disease, most likely due to its daily influence over metabolic cycles. Daily cell cycles are fundamental to normal operation of genetic mechanisms that control how cells grow and divide, both in normal development and in cancer.
The cellular mechanisms of diabetes, another chronic disease, are also tied to metabolic cycles controlled by the biological clock. For instance, the conversion of sugars into fat, which normally occurs only at certain times of day, often seems to take place all day long in diabetics' bodies, suggesting the clock has lost control.
"So much of what it means to be healthy and youthful comes down to a good night's sleep," Panda says. "Now that we have identified JARID1a in activating our daytime cycle, we have a whole new avenue to explore why some people's circadian rhythms are off and to perhaps find new ways to help them."
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 | EurekAlert!
Don't Give the Slightest Chance to Toxic Elements in Medicinal Products
23.03.2018 | Physikalisch-Technische Bundesanstalt (PTB)
North and South Cooperation to Combat Tuberculosis
22.03.2018 | Universität Zürich
Satellites in near-Earth orbit are at risk due to the steady increase in space debris. But their mission in the areas of telecommunications, navigation or weather forecasts is essential for society. Fraunhofer FHR therefore develops radar-based systems which allow the detection, tracking and cataloging of even the smallest particles of debris. Satellite operators who have access to our data are in a better position to plan evasive maneuvers and prevent destructive collisions. From April, 25-29 2018, Fraunhofer FHR and its partners will exhibit the complementary radar systems TIRA and GESTRA as well as the latest radar techniques for space observation across three stands at the ILA Berlin.
The "traffic situation" in space is very tense: the Earth is currently being orbited not only by countless satellites but also by a large volume of space...
An international team of researchers has discovered a new anti-cancer protein. The protein, called LHPP, prevents the uncontrolled proliferation of cancer cells in the liver. The researchers led by Prof. Michael N. Hall from the Biozentrum, University of Basel, report in “Nature” that LHPP can also serve as a biomarker for the diagnosis and prognosis of liver cancer.
The incidence of liver cancer, also known as hepatocellular carcinoma, is steadily increasing. In the last twenty years, the number of cases has almost doubled...
In just a few weeks from now, the Chinese space station Tiangong-1 will re-enter the Earth's atmosphere where it will to a large extent burn up. It is possible that some debris will reach the Earth's surface. Tiangong-1 is orbiting the Earth uncontrolled at a speed of approx. 29,000 km/h.Currently the prognosis relating to the time of impact currently lies within a window of several days. The scientists at Fraunhofer FHR have already been monitoring Tiangong-1 for a number of weeks with their TIRA system, one of the most powerful space observation radars in the world, with a view to supporting the German Space Situational Awareness Center and the ESA with their re-entry forecasts.
Following the loss of radio contact with Tiangong-1 in 2016 and due to the low orbital height, it is now inevitable that the Chinese space station will...
Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP, provider of research and development services for OLED lighting solutions, announces the founding of the “OLED Licht Forum” and presents latest OLED design and lighting solutions during light+building, from March 18th – 23rd, 2018 in Frankfurt a.M./Germany, at booth no. F91 in Hall 4.0.
They are united in their passion for OLED (organic light emitting diodes) lighting with all of its unique facets and application possibilities. Thus experts in...
A new scenario seeking to explain how Mars' putative oceans came and went over the last 4 billion years implies that the oceans formed several hundred million...
23.03.2018 | Event News
19.03.2018 | Event News
16.03.2018 | Event News
23.03.2018 | Materials Sciences
23.03.2018 | Agricultural and Forestry Science
23.03.2018 | Physics and Astronomy