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In gene regulation, small is beautiful


University of Michigan chemists have used small molecules to take a big step forward in controlling gene activity.

Scientists have been trying for some time to develop molecules that mimic natural regulators of gene expression. These natural regulators, called transcription factors, prompt particular genes to be active or to stay quiet. Their role is crucial, because errors in gene regulation can lead to diseases ranging from diabetes to cancer. Creating synthetic versions, known as artificial transcription factors or ATFs, could help scientists probe gene regulation and perhaps lead to new treatment approaches.

Both natural transcription factors and their artificial counterparts typically have two essential parts: a DNA-binding domain that homes in on the specific gene to be regulated, and a regulatory domain that attaches itself to the cell’s machinery and activates or represses the gene.

Recently, U-M assistant professor of chemistry Anna Mapp and coworkers designed small molecules that mimic in a general way the features of natural transcriptional activators. In this research, published online in the Journal of the American Chemical Society earlier this month, small molecule artificial activation domains developed in Mapp’s lab were as effective as a natural activation domain at turning on genes.

Small molecules have great advantages as artificial gene regulators, said Mapp, who also will discuss the work Aug. 22 at a meeting of the American Chemical Society in Philadelphia. They are less likely than larger molecules to be degraded, and they should be easier to introduce into cells---features that would be critical if ATFs are to be used in treating disease.

Next, Mapp’s group plans to investigate exactly how their artificial activators work. "We haven’t rigorously proven that they function by the same mechanism as natural activators, but they seem to be quite analogous," she said. The researchers also will try attaching their activators to different DNA-binding domains to see if that affects their activity.

Nancy Ross-Flanigan | EurekAlert!
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