Experimental work proves theory that circadian body clock requires delay to function properly

Mar 25, 2011
Delay in the activation of the gene Cry1 ensures that the circadian clock of mammals properly functions and adjusts to daily and seasonal changes in the environment. © 2011 iStockphoto/TPopova

For more than 20 years, theoretical mathematical models have predicted that a delay built into a negative feedback system is at the heart of the molecular mechanism that governs circadian clocks in mammalian cells. Now, the first experimental proof of this theory has been provided by an international research team led by molecular biologists and information scientists from the RIKEN Center for Developmental Biology in Kobe. The demonstration of the feedback delay should lead to a better understanding of how cellular clocks function, and therefore how mammals adjust to the regular daily and seasonal changes in their environment. The work could also open the way to the development of treatments for circadian disorders, such as seasonal affective disorder, jet lag and even bipolar disorder.

Mammals not only show daily rhythms of waking and sleeping, but also body temperature, , and many other biological activities. The master cellular clocks that act as timers for these patterns are found in the suprachiasmatic nucleus of the brain. The is built around a negative feedback system involving cryptochrome (Cry) genes, which code for proteins that repress their own activation by binding with the products of two other genes Bmal1 and Clock. The whole clock system is orchestrated by the interaction of these proteins with a complex array of promoters and enhancers, genetic sequences that regulate .

Within these clock-gene regulators are short sequences often known as clock-controlled elements. Different clock-controlled elements bind with the different proteins likely to be prevalent at different times of the day or night. The researchers carefully modified these sequences, and observed the impact on of cells. They focused their studies in particular on the gene Cry1, and observed how the rhythm of its activity was affected by the modifications of clock-controlled elements within promoters and enhancers.

In addition to revealing a previously unknown clock-controlled element in the Cry1 promoter, the researchers also found that different combinations of clock-controlled elements led to different lengths of delay in the activation of Cry1. They demonstrated that this delay of Cry1 was required for the circadian clock to function.

Based on these findings, they proposed a simple model of the mammalian circadian clock and now want to construct it using artificial components. “We think further experimental and theoretical analyses of this minimal circuit will lead to a deeper understanding of the mammalian circadian clock,” say team members Rikuhiro Yamada and Maki Ukai-Tadenuma.

Explore further: Two-armed control of ATR, a master regulator of the DNA damage checkpoint

More information: Ukai-Tadenuma, M., Yamada, R.G., Xu, H., Ripperger, J.A., Liu, A.C. & Ueda, H.R. Delay in feedback repression by Cryptochrome 1 is required for circadian clock function. Cell 144, 268–281(2011). www.cell.com/abstract/S0092-8674(10)01437-6

add to favorites email to friend print save as pdf

Related Stories

Key factor combines day and night to hold back morning

Feb 18, 2011

As in manmade timepieces, the movements of the genetic clockworks that lie behind circadian cycles involve a remarkable amount of complexity. Researcher's from RIKEN's Laboratory for Systems Biology report ...

Team creates math model for circadian rhythm

Aug 27, 2007

The internal clock in living beings that regulates sleeping and waking patterns -- usually called the circadian clock -- has often befuddled scientists due to its mysterious time delays. Molecular interactions that regulate ...

Recommended for you

Japanese scientist resigns over stem cell scandal

Dec 19, 2014

A researcher embroiled in a fabrication scandal that has rocked Japan's scientific establishment said Friday she would resign after failing to reproduce results of what was once billed as a ground-breaking study on ...

'Hairclip' protein mechanism explained

Dec 18, 2014

Research led by the Teichmann group on the Wellcome Genome Campus has identified a fundamental mechanism for controlling protein function. Published in the journal Science, the discovery has wide-ranging implications for bi ...

User comments : 0

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.