Natural Change Can Turn Genes Down as Well as Off

Newswise — Researchers have discovered that a natural chemical process that usually turns off gene activity can sometimes work like a dimmer switch and instead simply turn down the activity.

The finding comes from a new study of a gene known as C/EBPa (for CAAT/enhancer-binding protein alpha). The gene is often far less active " a dim bulb " in lung-cancer cells and other malignancies than it is in normal cells, but scientists didn't know why until now.

This study shows that in lung-cancer cells the gene is shut down by a chemical change known as DNA methylation, and that the chemical change occurs along an unexpected place in the gene.

"This could be a new model for how DNA methylation can regulate gene activity," says study leader Christoph Plass, professor of molecular virology, immunology and medical genetics and a researcher with The Ohio State University Comprehensive Cancer Center.

The findings, which are published in the March 15 issue of the Journal of the National Cancer Institute, suggests that the gene might be a good target for drugs that reverse DNA methylation. Changes in the gene might also one day serve as a marker for the early detection of lung cancer or indicate whether a particular therapy is working.

"This is the first example I know of where DNA methylation has not completely shut down a gene but instead is regulating its activity," Plass says.

Cells normally use DNA methylation to silence genes that are no longer needed, such as those required only during embryonic development. In cancer cells, however, the same process can silence genes that would normally protect cells from becoming cancerous.

Scientists have looked for DNA methylation in C/EBPa to explain the gene's low activity in cancer cells, but found none.

The problem was that they looked for the chemical change only in the usual places. Plass and his collaborators decided to look further a-field along the gene.

A gene is like a long sentence that describes the structure of a protein. The letters in the sentence are spelled out in the building blocks of the DNA strand of which the gene is part.

Like a sentence, a gene has a well-defined starting point, called the start site. Unlike a sentence, a gene has a second region that runs to the left of the start site. That region is known as the promoter, and this is the off-and-on switch for the gene.

DNA methylation involves chemical changes that take place in the promoter region. These changes alter the gene so that it cannot be turned on. Usually, these chemical changes occur in areas of the promoter that are close to the start site, and that's where others have looked for them in the C/EBPa gene.

Plass and his colleagues, however, looked two to three times farther from the start site than usual.

"We were surprised to find that methylation had occurred along this region far upstream from the start site," Plass says.

Because the promoter region close to the start site was unchanged, the gene can continue to be active, but only at a low level, he says.

"This suggests that we may have to consider examining regions of genes, and maybe even other regulatory sequences, that have been neglected in the past," he says.

Next, Plass and his colleagues will repeat this investigation in leukemia cells, where C/EBPa also shows dim activity but no DNA methylation near the start site.

A Translational V-Foundation Award and a grant from the Dr. Mildred Scheel Foundation for Cancer Research supported this research. Christoph Plass is a Scholar of the Leukemia and Lymphoma Society of America.