Researchers at Washington University School of Medicine in St. Louis have begun unraveling the network of genes and proteins that regulate the lives of cells. The investigators compared the genome of the yeast Saccharomyces cerevisiae (S. cerevisiae) to those of five other yeast species to identify all the locations at which molecules known as regulatory proteins attach to DNA to turn genes on and off. The study is published in the May 30 issue of the journal Science.
Among the many potential sites of gene regulation, 79 were predicted to be definitive new regulatory sites. The investigators also discovered 43 new genes and determined that 515 suspected genes are not genes at all. The findings revised the estimated number of genes in the S. cerevisiae genome from 6,331 to 5,773.
"This is the first step in understanding the gene-regulation network in a simple cell," says principal investigator Mark Johnston, Ph.D., professor of genetics and interim chair of genetics. "This work also will provide guidelines for analyzing the regulatory network of human cells, which will be a much more complex task."
Regulatory sequences are important, Johnston notes, because they are the basis of development. For example, a liver cell differs from a brain cell not because they have different genes—both cells have the same set of genes—but because of the genes they use. And that’s determined by the regulatory sequences that activate one set of genes in the liver and another set in the brain. A variety of diseases, including cancer, are caused by problems in gene regulation.
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Identifying gene regulatory sites is not easy, however. These regions serve as docking sites for DNA binding proteins that turn the gene on or off. They lack the typical DNA patterns that help scientists recognize the body of the gene, which contains information about the structure of a protein.
Johnston and his colleagues compared the genomes of S. cerevisiae to five other yeast species, hypothesizing that the regions that were most alike in all six would be potential regulatory sites.
The investigators found about 8,000 of these conserved sites, about one-third of which already were known regulatory sequences. After eliminating the known sites from the total, the investigators searched for other evidence that these sites are functional, and pinpointed 79 sites located within or near genes which are excellent candidates for new regulatory sequences.
The team will is now refining the number of sites by determining which yeast regulatory proteins bind to the them. "Now," Johnston says, "we can begin tackling the really interesting question: how a relatively small number of regulatory proteins coordinate the activity of more than 5,700 genes to maintain a healthy, growing yeast cell."
Cliften P, Sudarsanam P, Desikan A, Fulton L, Fulton B, Majors J, Waterston R, Cohen BA, Johnston M. Finding functional features in Saccharomyces genomes by phylogenetic footprinting. Science, May 30, 2003. Funding from the National Institute of General Sciences supported this research.