Pathway identification imperils disease

The development of a technique for identifying control elements that drive the expression of genes in brain cells could unleash the disease-fighting potential of the much-hailed human genome, maintains a study by Oregon Health & Science University, Portland.

"The question was how to understand the enormous amount of genomic information that has been generated," explains Richard Goodman, professor of cell and developmental biology. "Our approach will help unlock the regulatory control of the genome," as well as heighten understanding of the pathways behind genetic aberrations that cause diabetes, Parkinson's disease, heart disease, cancer, and other maladies.

The technique, developed in collaboration with scientists at Brookhaven National Laboratory, Upton, N.Y., and State University of New York, Stony Brook, resulted from attempting to characterize a family of genes regulated by the "cAMP response element binding" protein, or CREB. This well-characterized molecule is among a group of proteins called transcription factors that interact with regulatory elements in DNA that are responsible for increasing or decreasing the level of gene expression in cells.

The technique involves linking DNA from a cell with the transcription factor protein, then isolating the complex through a process called immunoprecipitation. Strips of 21-nucleotide-long DNA subsequently are released from the immunoprecipitated DNA to create "genomic signature tags," which subsequently are identified in the international genome database. The method uncovered about 6,300 regulatory regions that mapped to distinct sites on the genome. "A subset of these regions highlight novel genes," reports School of Medicine researcher Soren Impey.

Goodman calls the process "the most comprehensive analysis to date in a metazoan system--that is, a multicellular system--of where transcription factors bind to their genomic targets." It gives scientists a system for mining the entire genome for all the regulatory sites involving a given transcription factor protein.

"You can start to put together a transcriptional map of pathways that are involved in cellular function," he concludes. "In the past, it's only been possible to look at a very small part of the genome, but now we can look at the whole thing. It's a big step forward."

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