Our genome, we are taught, operates by sending instructions for the manufacture of proteins from DNA in the nucleus of the cell to the protein-synthesizing machinery in the cytoplasm. These instructions are conveyed by a type of molecule called messenger RNA (mRNA).
Francis Crick , co-discoverer of the structure of the DNA molecule, called the one-way flow of information from DNA to mRNA to protein the “central dogma of molecular biology.”
Yehuda Ben-Shahar and his team at Washington University in St. Louis have discovered that some mRNAs have a side job unrelated to making the protein they encode. They act as regulatory molecules as well, preventing other genes from making protein by marking their mRNA molecules for destruction.
“Our findings show that mRNAs, which are typically thought to act solely as the template for protein translation, can also serve as regulatory RNAs, independent of their protein-coding capacity,” said Ben-Shahar, an assistant professor of biology in Arts & Sciences. “They’re not just messengers but also actors in their own right.” The finding was published in the March 18 issue of the new open-access journal eLife.
Although Ben-Shahar’s team, which included neuroscience graduate student Xingguo Zheng and collaborators Aaron DiAntonio, MD, PhD, professor of developmental biology at the School of Medicine, and his graduate student Vera Valakh, was studying heat stress in fruit flies when they made this discovery, he suspects this regulatory mechanism is more general than that.
Many other mRNAs, including ones important to human health, will be found to be regulating the levels of proteins other than the ones they encode. Understanding mRNA regulation may provide new purchase on health problems that haven’t yielded to approaches based on Crick’s central dogma.
Is gene expression regulated directly?
Ben-Shahar’s original objective was to better understand how organisms maintain their physiological balance when they are buffeted by changes in the environment.
Neuroscientists know that if you warm neurons in culture, he said, the neurons will fire more rapidly. And if the culture is cooled down, the neurons slow down. Neurons in an organism, however, behave differently from those in a dish. Usually the organism is able to cushion its nervous system from heat stress, at least within limits. But nobody knew how they did this.
As a fruit fly scientist, Ben-Shahar was aware that there are mutations in fruit flies that make them bad at buffering heat stress, and this provided a starting point for his research.
One of these genes is actually called seizure, because flies with a broken copy of this gene are particularly sensitive to heat. Raising the temperature even 10 degrees sends them into seizures. “They seize very fast, in seconds,” Ben-Shahar said.
“When we looked at seizure (sei) we noticed that there is another gene on the opposite strand of the double-stranded DNA molecule called pickpocket 29 (ppk29),” Ben-Shahar said. This was interesting because seizure codes for a protein “gate” that lets potassium ions out of the neuron and pickpocket 29 codes for a gate that lets sodium ions into the neuron.
Neurons are “excitable” cells, he said, because they tightly control the gradients of potassium and sodium across their cell membranes. Rapid changes in these gradients cause a nerve to “fire,” to stop firing, and to repolarize, so that it can fire again.
The scientists soon showed that transcription of these genes is coordinated. When the flies are too hot, they make more transcripts of the sei gene and fewer of ppk29. And when the flies cooled down, the opposite happened. If the central dogma held in this case, the neurons might be buffering the effects of heat by altering the expression of these genes.
One problem with this idea, though, is that gene transcription is slow and the flies, remember, seize in seconds. Was this mechanism fast enough to keep up with sudden changes in the environment?
Does RNA interference regulate gene expression?
But the scientists had also noticed that the two genes overlapped a bit at their tips. The tips, called the 3′ UTRs (untranslated regions), don’t code for protein but are transcribed into mRNA.
That got them thinking. When the two genes were transcribed into mRNA, the two ends would complement one another like the hooks and loops of a Velcro fastener. Like the hooks and loops, they would want to stick together, forming a short section of double-stranded mRNA. And double-stranded mRNA, they knew, activates biochemical machinery that degrades any mRNA molecules with the same genetic sequence.