Scientists at Washington University in St. Louis say they have discovered that some messenger RNAs (mRNAs) not only play a direct role in manufacturing proteins but they also can act as regulatory molecules 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 Yehuda Ben-Shahar, Ph.D., a member of the research team. “They're not just messengers but also actors in their own right.”
The study (“Natural antisense transcripts regulate the neuronal stress response and excitability”) finding was published in eLife.
Although the scientists were studying heat stress in fruit flies when they made this discovery, Dr. Ben-Shahar suspects this regulatory mechanism is more general than that.
As a fruit fly scientist, Dr. 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.
“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),” he explained. 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.
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 of DNA (DNA to RNA to protein) 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?
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.
“We demonstrate that the mRNA 3′UTR of ppk29 affects neuronal firing rates and associated heat-induced seizures by acting as a natural antisense transcript (NAT) that regulates the neuronal mRNA levels of seizure (sei), the Drosophila homolog of the human Ether-à-go-go Related Gene (hERG) potassium channel,” wrote the investigators. “We find that the regulatory impact of ppk29 mRNA on sei is independent of the sodium channel it encodes. Thus, our studies reveal a novel mRNA-dependent mechanism for the regulation of neuronal excitability that is independent of protein-coding capacity.”
Dr. Ben-Shahar believes 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 insights on health problems that haven’t yielded to other approaches, he pointed out.