In a region of DNA long considered a genetic wasteland, Harvard Medical School researchers have discovered a new class of gene. Most genes carry out their tasks by making a product--a protein or enzyme. This is true of those that provide the body's raw materials, the structural genes, and those that control other genes' activities, the regulatory genes. The new one, found in yeast, does not produce a protein. It performs its function, in this case to regulate a nearby gene, simply by being turned on.
Joseph Martens, Lisa Laprade, and Fred Winston found that by switching on the new gene, they could stop the neighboring structural gene from being expressed. "It is the active transcription of another gene that is regulating the process," said Martens, HMS research fellow in genetics and lead author of the June 3 Nature study.
"I cannot think of another regulatory gene such as this one," said Winston, HMS professor of genetics. The researchers have evidence that the new gene, SRG1, works by physically blocking transcription of the adjacent gene, SER3. They found that transcription of SRG1 prevents the binding of a critical piece of SER3's transcriptional machinery.
The discovery raises tantalizing questions. How does this gene-blocking occur? Do other regulatory genes work in this fashion? Does the same mechanism occur in mammals, including humans?
At the same time, SRG1 provides clues to a recent puzzle. Researchers have lately begun to suspect that the long stretches of apparently useless, or junk, DNA might possess a hidden function. In the past year, evidence has been pouring in, not just from yeast but from mammals, that these apparently silent regions produce RNAs, which are associated with transcriptional activity (see Focus, March 5, 2004). Yet no one has found associated protein products. "For us it is easy to look at those findings and say, 'Well maybe those are examples of what is going on here in yeast,'" said Martens.
If so, the findings would carry an important message for the posthuman genome era--namely, that researchers' attempts to turn the masses of data churned out by the Human Genome Project into an understanding of what actually happens in the human body may be even more complex than they anticipated. One of the main challenges for that effort is to figure out how and when genes are turned on and off during normal development and disease. Rather than look only at how genes are regulated by proteins, they would have to turn their attention to a new, and possibly more-difficult-to-detect form of control. And given that junk DNA makes up 95 percent of chromosomes, the mechanism could be fairly common.
"I think if nothing else, this sends up an alert that this likely occurs in other cases," said Winston. "When people are looking to understand regulation of genes from whatever organism--humans, flies, mice, yeast--they cannot just look for proteins that are acting there. It might be that it is simply the act of transcribing that is causing regulation."
Like many researchers, Winston and his colleagues may have known in the back of their minds that someday they would have to contend with junk DNA, but it was not their intention to map a new gene in those wild and relatively uncharted regions of the chromosome. If anything, the yeast SER3 gene was their lodestar. What intrigued them about the gene, which is involved in the synthesis of the amino acid serine, was its unusual expression pattern. To be turned on, genes must first be bound by an activator molecule. A common activator in yeast is a molecule called Switch/Sniff. While most genes are turned on by Switch/Sniff, SER3 is turned off by the complex.
In the course of exploring how this repression happens, Martens came across an even more surprising result. "The usual story when a gene is transcriptionally repressed is that RNA polymerase, TATA binding protein and a host of other factors associated with active transcription, will not be there," he said. He, Laprade, a research associate, and Winston conducted a series of experiments and found that the factors were all present and active, and they were located just upstream of the SER3 promoter--as was a jot of DNA needed for the onset of transcription, the TATA element.