Enzyme Alarm Clock

Researchers have isolated a protein that sounds our biological clock’s alarm each morning, a new study reports.

Energy-saving tip: try replacing your alarm clock with a live rooster!

A gene known as KDM5A codes for an enzyme (i.e., a protein that increases the rate of a chemical reaction) called JARID1a. This enzyme acts as a switch that starts the biochemical process of waking us from sleep – like some kind of weird molecular rooster.

Here’s the background: scientists have known for years that levels of a protein called PER rise in the morning and fall toward nighttime. The level of PER in our bodies helps our cells know what time of day it is – higher levels tell us it’s time to be awake, while lower levels help make us sleepy. This wake/sleep process is known as the circadian rhythm or circadian cycle.

Two genes – known as CLOCK and BMAL1 – help raise levels of PER. When those levels reach a certain critical point in the evening, CLOCK and BMAL1 stop triggering a rise in PER levels – and as those levels drop, our heart rate, blood pressure, and mental activity slow down in preparation for bedtime.

But this research marks a new discovery: a specific enzyme that restarts the circadian cycle in the morning, telling CLOCK and BMAL1 to start raising PER levels again.

As the journal Science reports, a team led by Satchindananda Panda at Salk’s Regulatory Biology Laboratory collaborated with teams at McGill University and Albert Einstein College of Medicine to discover JARID1a’s role in the circadian cycle. The teams genetically engineered fruit flies to under-produce JARID1a, and these flies seemed to have no idea what time of day it was – they woke and slept at random hours, and took naps throughout the day… much like college students.

Human and mouse cells engineered to produce less JARID1a also produced odd levels of PER:

JARID1a increased histone acetylation by inhibiting histone deacetylase 1 function and enhanced transcription by CLOCK-BMAL1 in a demethylase-independent manner. Depletion of JARID1a in mammalian cells reduced Per promoter histone acetylation, dampened expression of canonical circadian genes, and shortened the period of circadian rhythms.

In other words, less JARID1a led to shorter circadian cycles of PER production in the cells.

But wait – there’s more! Panda and his team also discovered that JARID1a counteracts the effects of a protein called HDAC1, which acts as a molecular brake on CLOCK and BMAL1 each night. From this, the scientists reason that rising levels of PER tell HDAC1 to put the brakes on its own production as the night goes on, which would eventually allow JARID1a to restart the cycle by kicking CLOCK and BMAL1 back into gear, which would start raising PER levels again. Now how’s that for an intricate clock?!

The researchers confirmed this idea by inserting the JARID1a gene into the fruit flies that lacked it – and sure enough, JARID1a released the HDAC1 brake and put the flies on a normal circadian cycle.

Scientists hope this discovery will aid the development of certain types of drugs – for instance, as people age, their circadian cycles seem to shorten, and the researchers suspect this may have something to do with JARID1a. People with certain types of diabetes also tend to have out-of-whack circadian rhythms, so similar drugs might benefit them as well.

As for nocturnal college students and rockstars, though, I suspect the solution may not be quite so simple.

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