Researchers Build Diagram of Cell Cycle Clock

CAMBRIDGE, Mass. — For the first time, researchers at the Whitehead Institute have mapped the complete circuit of one of life's most fundamental processes—the cell cycle, which tells cells when to divide. This network diagram describes the genetic switches and connections that form the circuit common to a process found in all living organisms, from bacteria to human beings. The findings were published in the September 21 issue of Cell by Whitehead Member Richard Young and his colleagues.

"This study is important because it shows for the first time that we can use a technique called genome-wide location analysis to map the circuitry underlying many fundamental life processes," says Young, whose lab developed this technique six months ago. "We now have a technique to connect the control switches that make up the network for any living process you can think of—memory, digestion, aging. In turn, this will shed light on many diseases, which are basically breaks in the circuit."

Mapping the circuits of fundamental processes in health and disease is one of the next steps of the Human Genome Project, which identified the genetic parts list for these processes but not the connections that make life run. Scientists agree that deciphering these circuits is important, but this is the first study to show that it can be done, and therefore provides reason for excitement in the scientific community, say the authors.

The cell cycle is one of life's most important processes, dictating cell division in virtually all aspects of life. Understanding the fundamental cycle of how a cell knows when to divide is key to finding out what goes wrong in diseases such as cancer, where cells divide uncontrollably.

During cell division several events have to occur in an orderly sequence—for instance, the chromosomes of the cell duplicate, the two sets of chromosomes segregate, and the cell splits into two daughter cells. Though scientists knew about the separate stages of the cell cycle, they didn’t fully understand how the switches for each step were connected to the next one or what controlled them. To understand the process, the Young lab focused on nine master switches that are involved in the baker’s yeast cell cycle.

Itamar Simon, a postdoctoral fellow in the Young lab and first author on the Cell paper, mapped how the cell cycle in yeast is controlled by the nine proteins called transcriptional activators. These proteins bind to genes to turn them on, so the corresponding proteins necessary for a certain cell cycle stage are produced.

Simon found that a transcriptional activator from one stage of the cell cycle also activates transcriptional activators in the next stage of the cell cycle–creating a series of switches connected in a circular network. "It makes elegant sense that the cell cycle is controlled through a circular network, but that wasn’t anticipated. We now see that the network that controls the cell cycle is itself a cycle of regulators regulating regulators. Until recently, we didn’t have a technique to probe this kind of problem," says Simon.

Simon used a technique developed in the Young lab, which was published in Science last December. The technique involves first fixing DNA-binding proteins in living cells to their binding sites using chemical cross-linking methods and then breaking open the cells to create a molecular soup of DNA-protein complexes. Specific antibodies coupled with magnetic beads are then used to fish out DNA fragments cross-linked to the proteins. This provides researchers with a population of DNA-protein complexes, and unhooking the cross-linked DNA from the protein leaves them with DNA fragments that bind to proteins of interest. The researchers then label these fragments with fluorescent dye and hybridize them to a DNA array containing genomic DNA from yeast to reveal their identity.

This technique provides direct information that can’t be deduced from DNA arrays, which are useful in determining a cell’s expression profile (a snapshot of which genes are turned on and off in a cell) at a moment in time. A change in the cell’s environment can trigger a cascade of changes inside the cell, all of which can be captured in another snapshot. Though this provides information about what is going on in cell from one moment to the next, it doesn’t tell what is regulating the changes.

Understanding how biological processes are regulated on a genomic scale is a fundamental problem for the coming decades. "The pharmaceutical industry is based on therapeutics developed for correcting faulty protein products, which result from breakdowns in metabolic pathways. A new area of pharmaceutical industry will develop based on drugs targeting breakdowns in genome regulatory networks. Perhaps we can correct some problems even before a faulty protein is produced," predicts Young.