A Day in the Life of the Cell

We are all familiar with our daily cycles of sleep and wakefulness, but did you know that almost every cell in our bodies contains a 24-hour biological clock known as a “circadian” clock? 

Crystal structure of CLOCK:BMAL1
Figure 1: Crystal structure of CLOCK:BMAL1. Ribbon diagram of CLOCK:BMAL1 heterodimer. CLOCK subunit is green, and BMAL1 is blue. Each individual domain is labeled. Linker regions between domains in the two subunits (L1 and L2) are highlighted red or orange. Flexible loops lacking density are indicated by dotted lines.
© 2012 American Association for the Advancement of Science.

In the last year, Joseph Takahashi, Ph.D., Professor and Chair of the Department of Neuroscience at UT Southwestern Medical Center, and colleagues have made two major discoveries concerning the inner workings of the circadian clock at the molecular level. 

First, Dr. Takahashi, a Howard Hughes Medical Institute investigator, in collaboration with Hong Zhang, Ph.D., Associate Professor of Biophysics, solved the 3D atomic structure of the CLOCK:BMAL1 protein complex that drives circadian rhythms within individual cells. This is the first view of the atomic structure of this component of the molecular timepiece and was published in Science on July 13, 2012.

Second, senior research associate Nobuya Koike, Ph.D., Takahashi, Tae-Kyung Kim, Ph.D., Assistant Professor of Neuroscience, examined where and when the clock proteins, CLOCK, BMAL1, PER and CRY, act within the genome of cells using next-generation DNA sequencing methods. 

In liver cells, the researchers found that the clock proteins bind to tens of thousands of sites in the genome in a 24-hour rhythmic pattern to control the activity of thousands of genes each day. 

They were surprised to find that the majority of these “downstream” clock-regulated genes were coordinated or synchronized to turn on at the same time each day.  To understand how this might occur, the scientists went on to examine the molecular machine that governs the readout or “transcription” of genes (known as RNA polymerase II or “Pol II”).

Here they found another surprise: the circadian clock regulates the molecular machine Pol II across the entire genome on a daily basis.

How this might occur is unclear, but it is known that when Pol II is transcribing, the configuration of DNA is altered by chemical modifications on histone proteins that package DNA in the nucleus.  The packaged DNA in cells is known as “chromatin.”

When the team examined these “histone marks,” they found yet another surprise: the circadian clock regulates the conformation of chromatin across the entire genome on a daily basis.  Thus, the circadian clock acts at a fundamental level in cells to modulate chromatin DNA and the molecular machine Pol II. This work was published in Science on October 19, 2012.

Circadian transcriptional landscape
Figure 2: Circadian transcriptional landscape. Phase distributions of circadian transcriptional regulators, nascent RNA transcripts, RNA polymerase II (RAPII) occupancy, and histone modification rhythms in mouse liver. Mean circular phase of peak binding is indicated under the name.
© 2012 American Association for the Advancement of Science.