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Team Identifies, Maps Human Promoter Sequences, Reveals Links to Disease

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It is possible to identify and map all of the promoter sequences in the human genome and reveal their relevance to disease, according to research conducted by scientists at the Ludwig Institute for Cancer Research, NimbleGen Systems, and the University of California, San Diego.

The paper, published in the current issue of Nature, demonstrates a general methodology to comprehensively identify promoter sequences in the genome.

New drug targets may also result from information generated by promoter mapping, according to Bing Ren, the senior author of the study and an assistant professor of cellular and molecular medicine at UCSD. With "gene-regulatory networks" for each cell type that might result from the group's method, drugs could be developed to target specific regulatory pathways to correct gene expression gone awry, such as that of cancer, said Ren.

"Currently there are experimental therapeutic approaches being tested to correct gene expression — there is a company called Sangarmore that makes artificial transcription factors that turn genes on or off, [and] can be used in gene therapy," said Ren, by way of example.

But in the near term, the research may be able to prove the relevance of many non-coding SNPs to gene expression, and by extension, disease. "One immediate impact would be — you can combine our data with a SNP database, and prioritize the importance of those SNPs in affecting gene expression," said Ren.

NimbleGen provided the LICR researchers microarrays representative of "the entire genome, including promoter sequences," but excluding repeating sequences, said Ren. "Our approach is different from the conventional approach, in that we're not looking at sequence patterns, but we're looking at proteins that bind to promoters, and using these as markers to detect promoters," Ren said.

The group cross-linked proteins to promoters in the genomes of living cells of a single type, extracted the DNA, and fished out specific DNA-binding proteins using antibodies. From there, all that was left was to identify the DNA fragments with NimbleGen's microarrays.

The researchers' maiden run focused on RNA polymerase, but the method could be hypothetically targeted to any promoter-binding protein. "One caveat, though, is that not all genes are expressed in a single cell type, so the map that we made corresponds only to the active promoters for that cell type," Ren said. The group's study used fibroblast cells for the Nature article.

The approach should prove to be less biased and more comprehensive than a promoter-motif pattern, Ren said. "We still don't know precisely what sequence determines a promoter, but we know very well the set of proteins that work at the promoter to activate gene expression."

— Chris Womack ([email protected])

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