Nav: Home

Powering up the circadian rhythm

May 26, 2016

LA JOLLA--(May 26, 2016) At noon every day, levels of genes and proteins throughout your body are drastically different than they are at midnight. Disruptions to this 24-hour cycle of physiological activity are why jet lag or a bad night's sleep can alter your appetite and sleep patterns for days--and even contribute to conditions like heart disease, sleep disorders and cancers.

Now, scientists at the Salk Institute and collaborators have discovered a key player--a protein called REV-ERBα--that controls the strength of this circadian rhythm in mammals. The discovery is unusual in the field, as most circadian genes and proteins only shift the timing or length of the daily cycle.

"Whether it is Beethoven's 9th Symphony on your stereo or the symphony of genes in our bodies, both require volume to be heard," says senior author Ronald Evans, director of Salk's Gene Expression Laboratory, a Howard Hughes Medical Institute investigator, and holder of the March of Dimes Chair in Molecular and Developmental Biology. "Our recent work describes how REV-ERBα acts as a molecular conductor to allows the volume or activity of thousands of genes to be dialed up or down."

Disrupting just the amplitude--or strength--component of the circadian cycle, Evans adds, was enough to alter hormone levels, including those that wake us up in the morning. This means that people with lower amplitude fluctuations of the genes might feel flat and have less energy during the day. The results are described in the May 26, 2016 issue of Cell.

Previous research in the field revealed genes that cycle on and off throughout the day and showed how altering these circadian genes can shift the timing of the cycle and make the circadian rhythm longer or shorter than 24 hours. In 2012, Evans' group showed that REV-ERBα bound to many of these circadian genes and acted as a brake, affecting when during the day or night they were expressed.

"We saw REV-ERBα interacting with all these circadian-related genes," says Xuan Zhao, a research associate in the Evans lab and first author of the new paper. "So we wanted to see if it had a more central role in circadian rhythms."

In the new work, the team analyzed levels and molecular characteristics of REV-ERBα in the livers of mice throughout the day. They found that after its levels peaked during the day, two proteins, CDK1 and FBXW7, interacted with REV-ERBα to help reduce its levels to a low point by the middle of the night.

When Evans and his colleagues targeted these proteins to block the degradation of REV-ERBα in the livers of mice, normal daily fluctuations in gene expression were suppressed, but the timing of the cycles wasn't affected. Interestingly, merely altering the amplitude of the gene expression oscillations profoundly affected metabolism, disrupting the levels of fats and sugars in the blood.

"This study provides compelling molecular evidence for a key role for the circadian clock in regulating glucose and lipid metabolism, and points to new potential avenues for therapeutic intervention," says Steve Kay, president of The Scripps Research Institute, who collaborated with Evans on the work.

The observation is the first time scientists have discovered a way to control the amplitude--rather than the timing--of the circadian cycle. Moreover, mice that lacked REV-ERBα developed fatty liver disease, stressing the importance of regulating the intensity of the cycle.

"We think that if you have a 'weak' circadian cycle, you can't get enough signal to affect physiology," says Zhao. "Conversely, having an extra 'strong' circadian cycle would probably not be good. Evolution has given us a Goldilocks, or 'just right,' circadian cycle that is optimal for our health."

The researchers hope to investigate whether pharmacological compounds that block CDK1 may have the potential to treat circadian rhythm disruptions.

"Pharmacologically, we can manipulate this system," says Michael Downes, a Salk senior scientist and a co-corresponding author of the paper. "The more we understand about how to do this, the better we can treat metabolic diseases and cancers related to the circadian cycle."
-end-
Other researchers on the study were Han Cho, Ling-Wa Chong, Katja Lamia, Sihao Liu, Annette R. Atkins, Ester Banayo, and Ruth T. Yu of the Salk Institute; Tsuyoshi Hirota of the University of California, San Diego; Xuemei Han and John R. Yates III of The Scripps Research Institute; and Christopher Liddle of the University of Sydney.

The work and the researchers involved were supported by grants from the Howard Hughes Medical Institute, National Institutes of Health, the Glenn Foundation for Medical Research, The Leona M. and Harry B. Helmsley Charitable Trust, Ipsen/Biomeasure, The Lawrence Ellison Foundation, the Samuel Waxman Cancer Research Foundation, Susan G. Komen, and the Glenn Foundation for Medical Research.

About the Salk Institute for Biological Studies:

Every cure has a starting point. The Salk Institute embodies Jonas Salk's mission to dare to make dreams into reality. Its internationally renowned and award-winning scientists explore the very foundations of life, seeking new understandings in neuroscience, genetics, immunology and more. The Institute is an independent nonprofit organization and architectural landmark: small by choice, intimate by nature and fearless in the face of any challenge. Be it cancer or Alzheimer's, aging or diabetes, Salk is where cures begin. Learn more at: salk.edu.

Salk Institute

Related Sleep Articles:

Baby sleeping in same room associated with less sleep, unsafe sleep habits
The American Academy of Pediatrics (AAP) recommends parents keep babies in the same room with them to sleep for the first year to prevent sudden infant death syndrome (SIDS).
Alternating skimpy sleep with sleep marathons hurts attention, creativity in young adults
Skimping on sleep, followed by 'catch-up' days with long snoozes, is tied to worse cognition -- both in attention and creativity -- in young adults, in particular those tackling major projects, Baylor University researchers have found.
Sleep trackers can prompt sleep problems
A researcher and clinician in the sleep disorders program in the Department of Behavioral Sciences at Rush University Medical Center and an associate professor at Rush University, Baron says use of these devices follows a pattern reflected in the title of the Sleep Medicine study: 'Orthosomnia: Are Some Patients Taking the Quantified Self Too Far?'
UW sleep research high-resolution images show how the brain resets during sleep
Striking electron microscope pictures from inside the brains of mice suggest what happens in our own brain every day: Our synapses -- the junctions between nerve cells -- grow strong and large during the stimulation of daytime, then shrink by nearly 20 percent while we sleep, creating room for more growth and learning the next day.
What is good quality sleep? National Sleep Foundation provides guidance
The National Sleep Foundation (NSF) recently released the key indicators of good sleep quality, as established by a panel of experts.
Homeless sleep less, more likely to have insomnia; sleep improvements needed
The homeless sleep less and are more likely to have insomnia and daytime fatigue than people in the general population, findings researchers believe suggest more attention needs to be paid to improving sleep for this vulnerable population, according to a research letter published online by JAMA Internal Medicine.
Losing sleep over discrimination? 'Everyday discrimination' may contribute to sleep problems
People who perceive more discrimination in daily life have higher rates of sleep problems, based on both subjective and objective measures, reports a study in Psychosomatic Medicine: Journal of Biobehavioral Medicine, the official journal of the American Psychosomatic Society.
Mouse mutants with sleep defects may shed light on the mysteries of sleep
The first unbiased genetic screen for sleep defects in mice has yielded two interesting mutants, Sleepy, which sleeps excessively, and Dreamless, which lacks rapid eye movement (REM) sleep.
Brain circuit that drives sleep-wake states, sleep-preparation behavior is identified
Stanford University School of Medicine scientists have identified a brain circuit that's indispensable to the sleep-wake cycle.
Recharge with sleep: Pediatric sleep recommendations promoting optimal health
For the first time, the American Academy of Sleep Medicine has released official consensus recommendations for the amount of sleep needed to promote optimal health in children and teenagers to avoid the health risks of insufficient sleep.

Related Sleep Reading:

Why We Sleep: Unlocking the Power of Sleep and Dreams
by Matthew Walker PhD (Author)

A New York Times bestseller

The first sleep book by a leading scientific expert—Professor Matthew Walker, Director of UC Berkeley’s Sleep and Neuroimaging Lab—reveals his groundbreaking exploration of sleep, explaining how we can harness its transformative power to change our lives for the better.

Sleep is one of the most important but least understood aspects of our life, wellness, and longevity. Until very recently, science had no answer to the question of why we sleep, or what good it served, or why we suffer such devastating health consequences when we... View Details


Sleep Smarter: 21 Essential Strategies to Sleep Your Way to A Better Body, Better Health, and Bigger Success
by Shawn Stevenson (Author)

When it comes to health, there is one criminally overlooked element: sleep. Good sleep helps you shed fat for good, stave off disease, stay productive, and improve virtually every function of your mind and body. That’s what Shawn Stevenson learned when a degenerative bone disease crushed his dream of becoming a professional athlete. Like many of us, he gave up on his health and his body, until he decided there must be a better way. Through better sleep and optimized nutrition, Stevenson not only healed his body but also achieved fitness and business goals he never thought possible.... View Details


Go the F**k to Sleep
by Adam Mansbach (Author), Ricardo Cortés (Illustrator)

"Nothing has driven home a certain truth about my generation, which is approaching the apex of its childbearing years, quite like this."
--The New Yorker

"A parenting zeitgeist"
--Washington Post

"A hilarious take on that age-old problem: getting the beloved child to go to sleep."
--National Public Radio

"A new Bible for weary parents"
--New York Times

"Resonates powerfully with almost everyone"
--Boston Globe

"Go the F*** to Sleep challenges stereotypes, opens up prototypes, and acknowledges that shared... View Details


The Sleep Fairy
by Janie Peterson (Author), Macy Peterson (Author)

HELP IS FINALLY HERE FOR PARENTS WHOSE CHILDREN JUST WON'T "STAY IN BED" AT BEDTIME. Helping children learn to stay in bed after they have been tucked in for the night is a challenge many parents face. With the help of Peterson's delightful book, The Sleep Fairy, now in an updated hardcover and better than ever second edition, families everywhere can have pleasant bedtimes. The Sleep Fairy is a proud recipient of the Mom's Choice Award for excellence in children's books. View Details


Go Sleep in Your Own Bed
by Candace Fleming (Author), Lori Nichols (Illustrator)

From bestselling, award-winning author Fleming and beloved illustrator of the Maple books Nichols comes a giggle-inducing read-aloud starring a cast of comically grumpy barnyard animals. Sure to become a bedtime favorite.
 
This funny and irresistible picture book feels like a classic in the making. When Pig plops into his sty at bedtime, he finds Cow fast asleep in his spot. "Go sleep in your own bed!" he squeals, and sends her packing. But when Cow finally snuggles down into her stall, she finds Hen sleeping there. So begins a chain reaction of snoozing barnyard... View Details


The Sleepeasy Solution: The Exhausted Parent's Guide to Getting Your Child to Sleep from Birth to Age 5
by Jennifer Waldburger (Author), Jill Spivack (Author)

Two experts who are helping Hollywood's A-list babies get their zzz's share the no-fail, family-friendly method that has helped thousands of sleep-deprived moms and dads.

Even Hollywood's biggest stars face the same dilemma as other parents do: "How do I get my child to sleep?" As parents in the know are finding, whether they're on the red carpet or the soccer field, the answer is the same: The Sleepeasy Solution.

Psychotherapists and sleep specialists Jennifer and Jill, the dynamic "girlfriends" all of Hollywood calls on to solve Junior's sleep problems,... View Details


Get Your Sleep On: A no-nonsense guide for busy moms who want to preserve attachment AND sleep through the night
by Christine Lawler (Author)

Sleep training. People talk about it like it’s so easy. But how do you do it in a way that fits your style, protects your relationship with baby and actually works? Don’t worry, I’ll tell you. In this quick and easy guide, I’ll distill all the basics from the best resources out there on baby sleep. I skip the parent shaming and a ton of fluff that the other books are filled with, and I’ll give you the best cliff’s notes version out there so that in an hour or so you can be a sleep-expert, too. I'll explain why sleep is so important, and tell you the biggest secret out there about... View Details


The Sleep Solution: Why Your Sleep is Broken and How to Fix It
by W. Chris Winter M.D. (Author)

With cutting-edge sleep science and time-tested techniques, The Sleep Solution will help anyone achieve healthy sleep and eliminate pills, pain, and fatigue.
 
If you want to fix your sleep problems, Internet tips and tricks aren’t going to do it for you. You need to really understand what’s going on with your sleep—both what your problems are and how to solve them.
 
The Sleep Solution is an exciting journey of sleep self-discovery and understanding that will help you custom design specific interventions to fit your lifestyle. Drawing on... View Details


Sleep No More: Six Murderous Tales
by P. D. James (Author), Peter Kemp (Foreword)

No one gets inside the head of the murderer—or makes it a more thrilling read—than the late, great P. D. James. Fast on the heels of her latest best seller: a new, fiendishly entertaining gathering of previously uncollected stories, from the author of Death Comes to Pemberley and The Private Patient.

It's not always a question of "whodunit?" Sometimes there's more mystery in the why or how. And although we usually know the unhealthy fates of both victim and perpetrator, what of those clever few who plan and carry out the perfect crime? The ones who aren't... View Details


Before I Go to Sleep: A Novel
by S. J. Watson (Author)

The New York Times bestseller, now available in paperback—a disturbing psychological thriller, reminiscent of Shutter Islandand Memento, in which an amnesiac desperately tries to uncover the truth about who she is and who she can trust.

“Thebest debut novel I’ve ever read.”—Tess Gerritsen,bestselling author of the Rizzoli & Isles series

“Anexceptional thriller. It left my nerves jangling for hours after I finished thelast page.” —Dennis Lehane, New York Times... View Details

Best Science Podcasts 2017

We have hand picked the best science podcasts for 2017. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Simple Solutions
Sometimes, the best solutions to complex problems are simple. But simple doesn't always mean easy. This hour, TED speakers describe the innovation and hard work that goes into achieving simplicity. Guests include designer Mileha Soneji, chef Sam Kass, sleep researcher Wendy Troxel, public health advocate Myriam Sidibe, and engineer Amos Winter.
Now Playing: Science for the People

#448 Pavlov (Rebroadcast)
This week, we're learning about the life and work of a groundbreaking physiologist whose work on learning and instinct is familiar worldwide, and almost universally misunderstood. We'll spend the hour with Daniel Todes, Ph.D, Professor of History of Medicine at The Johns Hopkins University, discussing his book "Ivan Pavlov: A Russian Life in Science."