NEWS

UNC scientists find they can tap gene-silencing process to reveal parts of genetic machinery that make it work

By DAVID WILLIAMSON
UNC News Services

CHAPEL HILL – In 1998, researchers discovered to their surprise a long-hidden but common form of gene silencing called "RNA interference." In that key biological process, double-stranded pieces of the genetic information known as RNA become potent brakes on gene activity.

RNA interference -- RNAi for short -- works in animal cells by degrading the messenger RNAs that serve as the mobile blueprints produced by genes.

Now, scientists at the University of North Carolina at Chapel Hill have discovered that RNAi itself can be exploited to rapidly identify parts of the machinery that makes RNAi work. With further research, the finding could have important implications for treating cancer and other serious illnesses, they say.

"We stumbled upon the finding," said Dr. Bob Goldstein, assistant professor of biology. "A graduate student in my lab, Nate Dudley, found that what was considered an annoying peculiarity of RNAi became, in the end, a really useful way to figure out how it works."

By injecting pieces of laboratory-produced, double-stranded RNA into worms, the researchers can "silence" just about any gene they want depending on the composition of the RNA they choose, he said.

"What we found was that if we silenced the activity of genes that are part of the RNA interference mechanism, we could turn off RNA interference," he said. "Since only a few pieces of the RNA interference machinery are known right now, we were excited to find that we can use this method to identify more pieces of the mechanism.

"Also, when we look at new parts of the machinery we have identified, they look like proteins that directly turn genes off," Goldstein said. "Since RNAi was only known to work in animal cells by degrading the messenger RNAs produced by genes, this too was a surprise."

A report on the discovery appears in the April 2 issue of the Proceedings of the National Academy of Sciences. Dudley, Goldstein and biology postdoctoral fellow Jean-Claude Labbe carried out the research. The team conducted its experiments in one-millimeter-long worms that live in soil and eat bacteria. Scientists call the critter Caenorhabditis elegans.

"The coolest thing about C. elegans is that it has all the major cell types that we have -- muscle, nerve, gut, skin and so on -- yet the whole worm contains only 959 cells," said Goldstein, a member of the biology department and Lineberger Comprehensive Cancer Center at UNC’s medical school. "C. elegans is therefore one of the simplest organisms available for studying how genes function during development. Human beings, on the other hand, have trillions of cells."

Many experiments, which would take forever or be impossible in humans can be done rapidly in C. elegans, he said. Eventually, scientists will determine whether what they learn about gene silencing from the worm model applies, as they expect, to mammals and humans as well.

"The worm is optically clear so we can see everything going on inside, and it goes through a complete generation in only three days," Goldstein said. "It was the first animal in which the complete genome was sequenced, and it is used by several hundred labs around the world to study an incredibly diverse array of biological phenomena, including aging, cancer and cell death."

Whether RNAi works similarly in humans is not yet clear, but since it appears so far to function essentially the same way in diverse animals, that’s a good bet, the biologist said.

Once RNA interference is mostly or entirely understood in organisms like the worm, scientists might be able to turn off gene expression at will, including genes responsible for cancer and various genetic disorders.

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Note: Goldstein and Dudley can be reached at (919) 843-8575 or bobg@unc.edu and ndudley@email.unc.edu