In the mouse liver, almost all DNA transcription occurs at the same time every day.

Fluctuations in the amounts of transcription factors result in a daily wave of genome-wide transcription.

Circadian clocks control significant bodily functions: sleeping and feeding patterns, blood pressure, hormone production, body temperature, brain activity. Now, HHMI investigator Joseph Takahashi at the University of Texas Southwestern Medical Center is adding genome-wide transcription to that list.

The circadian clock synchronizes biological processes with the day–night cycle. Its cogs consist of a few core proteins that act as transcription factors to maintain the body’s 24-hour rhythms. The transcription factors CLOCK, BMAL1, and NPAS2 are circadian activators—they turn genes on by unwinding DNA and recruiting the transcription enzyme RNA polymerase II. PER1, PER2, CRY1, and CRY2, on the other hand, are repressors that turn genes off by inhibiting other transcription factors.

Takahashi and his colleagues wanted a global view of how these cogs work. So they undertook an in-depth study of where and when these transcription factors bind to genes in the liver cells of mice. Much to their surprise, they uncovered a wave of genome-wide transcription that crests at the same time every evening.

		Circadian Landscape This graph shows the relative amounts of circadian transcriptional regulators, intron cycling RNA transcripts, and histone modifications throughout the day. View Graphic...

“At dawn, we find that CLOCK and BMAL are bound to DNA but there’s no transcription because these activators are being repressed by CRY1,” explains Takahashi. As he reported October 19, 2012, in Science, the two proteins are still actively recruiting RNA polymerase II, but transcription is stalled. Then, as daylight increases, the repressor departs and the activators begin unwinding DNA and preparing for transcription. After about 12 hours of daylight, RNA polymerase II begins genome-wide transcription in earnest, peaking in activity about 15 hours after sunrise. As night falls, the PER and CRY proteins return, halting the process and readying it for another round the next day.

It’s unclear if this phenomenon occurs in organs beyond the liver, which is highly rhythmic and does most of its work at night. Takahashi is investigating this question and is setting up experiments to test whether disrupting the sleep–wake cycles of mice shifts the timing of their transcriptional wave.

Illustration: Joseph Takahashi / University of Texas Southwestern Medical Center