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More than 3,000 epigenetic switches control daily liver cycles

Epigenetic Switches

Thousands of epigenetic switches in the liver control whether genes turn on or off in response to circadian cycles. The figure illustrates daily changes, every six hours, in five different features of chromatin associated with the timed expression of a gene (red track on top).

Salk findings may help explain connections between dietary schedules and chronic disease

When it's dark, and we start to fall asleep, most of us think we're tired because our bodies need rest. Yet circadian rhythms affect our bodies not just on a global scale, but at the level of individual organs, and even genes.

Now, Salk scientists have determined the specific genetic switches in mice that sync liver activity to the circadian cycle. Their finding gives further insight into the mechanisms behind health-threatening conditions such as high blood sugar and high cholesterol.

"We know that genes in the liver turn on and off at different times of day and they're involved in metabolizing substances such as fat and cholesterol," says Satchidananda Panda, co-corresponding author on the paper and associate professor in Salk's Regulatory Biology Laboratory. "To understand what turns those genes on or off, we had to find the switches."

In the case of humans and other vertebrates, a brain structure called the suprachiasmatic nucleus controls circadian responses. But there are also clocks throughout the body, including our visceral organs, which tell specific genes when to make the workhorse proteins that enable basic functions in our bodies, such as producing glucose for energy.

In the liver, genes that control the metabolism of fat and cholesterol turn on and off in sync with these clocks. But genes do not switch on and off by themselves. Their activity is regulated by the "epigenome," a set of molecules that signal to the genes how many proteins they should make, and, most impor - tantly from the circadian point of view, when they should be made.

To their surprise, the Salk scientists discovered that among those epigenetic switches was chromatin, the protein complex that tightly packages DNA in the cell nucleus. While chromatin is well known for the role it plays in controlling genes, it was not previously suspected of being affected by circadian cycles.

Panda and his colleagues, including Joseph R. Ecker, holder of the Salk International Council Chair in Genetics, reported their results in Cell Metabolism.