BioWorld International Correspondent

LONDON - A gene that plays a key role in rapidly dividing cells, such as are found in malignant tumors, is switched on and off by RNA derived from "junk" DNA, a new study has shown.

The discovery opens up a new dimension to the ways in which, in the future, it may be possible to manipulate the expression of various disease-causing genes.

Alexandre Akoulitchev, senior research fellow at the University of Oxford, told BioWorld International: "There is a lot of work to do before we can apply this finding in the form of new drugs. But this type of RNA shuts down gene expression specifically and efficiently by binding to the gene's promoter sequence. It can do this because of its complementary base sequence - and no other protein or designer drug of any other kind will provide the same affinities or the same specificity."

In five to 10 years, he predicted, "we will have different kinds of drugs, such as RNA, to control diseases that are caused by expression of the wrong genes at the wrong time, such as cancer and many other diseases."

Akoulitchev and his colleagues reported their work in a paper in the Jan. 21 issue of Nature titled "Repression of the human dihydrofolate reductase gene by a non-coding interfering transcript."

The group was studying the control of gene expression using a model system featuring the gene that encodes the enzyme dihydrofolate reductase (DHFR). That enzyme controls production of thymine, which is an essential raw material for rapidly dividing cells. DHFR is the target for the first anticancer drug, methotrexate, which acts by binding and inhibiting it.

"We were already aware that the ways in which the gene is regulated might include non-coding RNA - a type of RNA produced by DNA that is not responsible for producing proteins," Akoulitchev said. Recent research has shown that this "junk" DNA, which appears to have no function, produces about half a million varieties of RNA of unknown function.

As the Nature paper reported, the team showed that a non-coding RNA of "substantial size" can switch off the promoter of the DHFR gene, and do so specifically and efficiently. "Our results tell us that this is not a unique case - it is probably a common and efficient way for cells to switch on and off their protein production, or for us to use to design new drugs to carry out these functions," Akoulitchev said.

Unlike drugs that modify the protein produced by the gene of interest or interfere with the RNA transcript of the gene, the approach described in Nature involves simply triggering the "master switch" to turn gene production off or on, he explained.

Additional experiments showed that exactly the same control process was occurring in live cells. "The hallmarks of what is happening in vivo tell us that we will see non-coding RNA controlling the expression of many different genes, and maybe in an even more sophisticated way," Akoulitchev said. "We suspect that there are quite a few genes where non-coding RNAs will be regulating promoters in a much more sophisticated way, including controlling levels of expression as well as switching on and off."

The paper in Nature described how the non-coding RNA forms a complex with the major promoter of the DHFR gene, and how it interacts directly with the general transcription factor known as IIB.

DHFR, like many of the most interesting human genes, has several promoters, Akoulitchev said. "We need to understand the complex and ambiguous way in which these types of promoters are regulated if we want to control abnormal gene expression in various tumors," he added.

Next, the team plans to look at examples of other genes that are regulated in a similar way by non-coding RNAs. "We want to delineate the important details of the RNA-dependent regulatory mechanism," Akoulitchev said. "This will give us confidence and certainty in our move toward clinical applications."