What makes a biological clock tick? According to a new study, the surprising answer lies with a gene typically associated with stem and cancer cells.
In the first study of its kind for the field of circadian biology, researchers used RNA sequencing to observe the expression of genes in the suprachiasmatic nucleus (SCN), a tiny region of the brain's hypothalamus region that governs the biological clock in mammals. Their findings pinpoint a gene that appears to regulate the biological clock and act as "master control" of the central circadian pacemaker.
Previously, the researchers were studying Period2, a gene found in the SCN, and were surprised to observe that another gene known as SOX2 was also present in the same area. "We noticed that Period2 was always expressed in the same population of cells as those that are expressed in SOX2--the biological clock was one of the major brain regions where these two genes overlapped," says the senior author. "This is interesting because SOX2 is usually expressed in stem cells and in cancer cells, but we usually don't find it in large amounts in healthy adult brains or in neurons. We wondered if it might have a function that no one has previously thought about."
Using mouse models that were missing the SOX2 gene, the researchers observed rodent behavior under controlled environmental conditions. "A normal mouse with a functioning biological clock will start running on its wheel when the lights go off and will run through the night," says the lead author. "They stop and go to bed when the lights come on, but when we knock out SOX2, the mice don't seem to know what they're doing."
"It's like their clock is broken or wonky," adds the senior author. "It's not telling time properly." The mice missing SOX2 also displayed weak running activity and irregular sleeping patterns. "It was as if they were chronically jet-lagged," the lead author says, noting that the mice also had trouble adapting to new schedules. "They lost their rhythm, even with a small manipulation of light exposure," the author says. "Adapting to jet-lag is built into our biological clocks--that's how we can survive intercontinental travel. But the mice missing the SOX2 gene lost their ability to adapt."
"When we knocked out SOX2, we observed great changes in different gene networks in the SCN that were very important to its neural network functions," says the senior author. "We think that instead of regulating a single gene, SOX2 is coordinating the expression of many, many genes, and contributing to the function of the SCN as the master regulator of the circadian pacemaker." RNA sequencing revealed that Sox2 deficiency alters the SCN transcriptome, reducing the expression of core clock genes and neuropeptide-receptor systems.
Stem cell gene is a 'master pacemaker' for biological clocks
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