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Salk scientists redraw the blueprint of the body's biological clock
Date:4/6/2012

sts knew that two genes, BMAL1 and CLOCK, worked together at the core of the clock's molecular machinery to activate the network of circadian genes. In this way, BMAL1 acts like the accelerator on a car, activating genes to rev up our physiology each morning so that we are alert, hungry and physically active.

Prior to this work REV-ERBα and β were thought to play only a minor role in these cycles, possibly working together to slow CLOCK-BMAL1 activity to make minor adjustments to keep the clock running on time.

However, genetic studies of two genes with similar functions can be very difficult and thus the real importance of REV-ERBα and β remained mysterious.

The Salk scientists got around this hurdle by developing mice in which both genes could be turned off in the liver at any point by giving them an estrogen derivative called tamoxifen. Now mice could develop normally to adulthood, at which point the scientists could turn off REV-ERBα and REV-ERBβ in their livers ---- an organ crucial to maintaining the correct balance of sugar and fat in blood ---- to see what effects it had on circadian rhythms and metabolism.

"When we turned off both receptors, the animal's biological clocks went haywire," says Han Cho, first author on the paper and a postdoctoral researcher in Evan's laboratory. "The mice started running on their exercise wheels when they should have been resting. This suggested REV-ERBα and REV-ERBβ aren't an auxiliary system that makes minor adjustments, but an integral part of the clock's core mechanism. Without them, the clock can't function properly."

Digging more deeply into the clockworks, the Salk scientists mapped out the genes that the REV-ERBs control to keep the body operating on the right schedule, finding that they overlap with hundreds of the same genes controlled by CLOCK and BMAL1. This and other findings suggested that the REV-ERBs, act as a break on the g
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Contact: Andy Hoang
Ahoang@salk.edu
619-861-5811
Salk Institute
Source:Eurekalert  

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