� Salk Institute for Biological Studies
The circadian clock depicts a person’s regular
physiological events during certain hours of the day.

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.

� Salk Institute for Biological Studies
The circadian clock illustrates the many diseases
that manifest in a person during certain times of the day.

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.

Now that scientists understand why we wake each day, they can explore the role
of JARID1a in sleep disorders and chronic diseases, possibly using it as a
target for new drugs.

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.”