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Microarray technology identifies genes controlled by master switches
Techniques to be tested on 200 circuits in yeast
Charles W. Schmidt

Much of the complicated machinery that governs genome functioning is coordinated by DNA binding proteins scientists call 'master switches.' Each switch can control up to 100 genes involved in different aspects of genome expression and maintenance. Until recently, it could take years of effort to identify all the genes controlled by a single master switch. But researchers at the Cambridge, Massachusetts-based Whitehead Institute and Corning Inc. have developed a groundbreaking microarray technique that effectively shortens this time frame to as little as one week. The research group was led by Whitehead member Richard Young and the technique is described in the December 22 issue of Science.

One example of a master switch is the p53 protein, which targets several dozen genes involved in cell proliferation. Normally, p53 coordinates cellular processes that inhibit tumor growth. That capacity is eroded if the protein is defective—causing abnormal cells to proliferate uncontrollably and explaining p53's suspected role in more than 50 percent of all human cancers.

The first step in the new technique involves fixing DNA binding proteins in living cells using cross-linking methods. After rupturing the cells to liberate the genetic material, magnetic beads are used to extract DNA fragments cross-linked to the proteins of interest. Unhooking the proteins leaves a DNA strand that can be labeled with a fluorescent dye and hybridized in ways that reveal its unique identity. With this approach, the researchers were able to correctly identify the circuits for certain metabolic processes controlled by two master switches in yeast: Ga14 and Ste12.

Once the technique is further developed, it will be used to create a kind of "user's manual" matching the master switches to the circuits they control in the genome. According to Young, the current goal is to identify all the circuits controlled by the roughly 200 master switches in yeast before developing analogous techniques for use in humans.

The human genome contains roughly 1,000 master switches, 250 of which have been characterized to some extent. Identifying the functioning of all these switches in an accelerated fashion should constitute a fundamental step toward the ongoing search for the genetic basis of disease and the development of better drugs.

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Ren, B. et al. Genome-wide location and function of DNA binding proteins. Science 290, 2306-2309 (December 22, 2000).

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