To understand the human genome, scientists focused on protein-coding genes and their functions for decades. This has given us invaluable knowledge about the inner workings of the human body. But that also only accounts for about a bit of the genome. So what about the rest of it, which was written off as a kind of ‘junk DNA’ for many years? Advances in genetic technologies have enabled scientists to learn more about the so-called dark regions of the genome, and what they could actually be doing, while not coding for protein. It seems that many of these sequences, which can be transcribed into RNA molecules that have a biological effect, are often involved in regulating other parts of the genome.
Now, scientists want to search through long, non-coding RNA molecules to assess their potential as therapeutics. For this effort, a University of Toronto Engineering team is now thought to be the first to have synthesized long noncoding RNA (lncRNA) molecules in the lab. They are already finding some molecules that have potential as anti-inflammatory agents. The team is hopeful that one day lncRNAs could work as treatments for some conditions. The work has been reported in Science Signaling.
Researchers have found around 40,000 lncRNA molecules so far, and we don’t know very much about their function, but scientists now suspect that this ‘junk’ is actually very important.
"There's no way evolution would allow these lncRNAs to take up so much space in our genome unless they were giving us some kind of survival advantage," said senior study author Omar F. Khan, a Professor at the University of Toronto. “If we can figure out what these lncRNAs do, make them in the lab, and then administer them to sick patients like any other medicine, we could modify or enhance the body's natural processes to promote healing."
The researchers began by looking for lncRNA transcripts that have been associated with inflammation in previous studies, since chronic inflammation has been linked to so many disorders. They hoped to find molecules that might control inflammation, and might be used to reduce it when it becomes a problem.
Three lncRNAs have been linked to inflammation regulation in previous work: GAPLINC, MIST, and DRAIR. So the researchers engineered these molecules outside of cells, and then made a packaging and delivery system to send them to cells growing in culture, or mouse models of inflammatory disease.
"We found that each sequence reduced inflammation in a different way," said first study author Janice Pang, a graduate student in the Khan lab. “They did this by decreasing the production of specific cytokines, which are signaling proteins produced in the body that trigger inflammation."
Next, the investigators made modifications to the lncRNAs to boost their potency, and reduce the dosages sent to cells and animal models. This could make them more viable as therapeutic candidates.
While more testing will be needed, this approach could open up many new options for drug discovery and development.
"What's so great about these lncRNA sequences is that they've been honed by millions of years of evolution, so we know they're biocompatible with humans: they've already been de-risked, in a sense. On top of that, each lncRNA evolved to have a very narrow, specific mechanism of action. That specificity reduces the potential for side effects, and it also enables us to get the desired response with minimal doses,” added Khan.
"This is a completely new paradigm for drug discovery, and we think that the dark transcriptome is a great opportunity to find new treatments that will really change lives in the future."
Sources: University of Toronto, Science Signaling
