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Thursday, September 09, 2004In the past few years, biologists have churned out the entire genetic sequence of dozens of organisms, including humans, dogs, mosquitoes, rats, and bacteria. But these strings of genes amount to the most basic molecular parts list, not much more helpful to deciphering how the genes combine to run a living cell than an array of microchips and wires would be for assembling a computer. The much-heralded genome is just a parts list. New research is revealing when, and why, genes do what they do in living cells—a big step toward understanding, and ultimately curing, disease.Any cell, from yeast to human, uses multiple layers of control to coordinate which genes are switched on and off in response to stimuli such as temperature, nutrient availability, and outside chemical messengers. The central method of gene control, however, relies on proteins known as transcription factors. When these molecules attach to a region of DNA close to a particular gene, that gene is switched on; when the protein detaches, the gene shuts down. Mutations in transcription factors or in their binding sites on the genome are associated with many diseases, including hypertension, cancer, and diabetes.Finding the binding sites is key to understanding how they influence the cell, but locating these tiny stretches of the genome has been difficult. In the new study, the MIT/Whitehead team used arrays of short DNA sequences on so-called gene chips, along with pattern-finding computer algorithms, to quickly identify the precise binding sites for almost every transcriptional regulator used by baker’s yeast—what Young calls the genome’s “regulatory code.” In the mid-1980s, geneticists started learning how proteins such as transcription factors recognize DNA. “Finally, this is the next level,” says Marc Vidal, a geneticist at Harvard Medical School. Understanding how 203 proteins interact with all 6,000 yeast genes is crucial, he believes. Vidal adds that “trying to extract the rules of how you organize such a network is the really interesting question”—one that will lead to an appreciation of how genes actually work with one another to keep a cell functioning. A significant advancement indeed.
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