Researchers at the University of Maryland have discovered new pathways for double-stranded dsRNA to enter cells, revealing how RNA influences gene regulation over many generations – insights that could improve RNA-based drugs
RNA-based drugs are among the most promising approaches to combat human disease, as demonstrated by the success of RNA-based vaccines and recent double-stranded RNA (dsRNA) therapies. Although it is now possible to develop drugs that specifically target disease-causing genes and silence them using dsRNA, a significant challenge remains: efficiently delivering these essential RNA molecules into cells.
A new study published in eLife on February 4, 2025, could lead to breakthroughs in the development of RNA-based drugs. Researchers at the University of Maryland used microscopic roundworms (C. elegans) as a model system to study how dsRNA molecules naturally enter cells and affect multiple generations in the future. Their findings revealed several pathways for dsRNA to enter the worm’s cells—a discovery that could improve methods for delivering drugs to humans.
New insights into transfer RNA
“Our findings challenge previous assumptions about RNA transfer,” said the study’s lead researcher, Antony Jose, an associate professor of cell biology and molecular genetics at the University of Maryland. “We learned that RNA molecules can carry specific instructions not only between cells, but also across many generations. This adds a new layer to our understanding of how heredity works.”
The team discovered that a protein called SID-1, which serves as a gatekeeper for the transmission of information via dsRNA, also plays a role in regulating genes across generations. When the researchers removed the SID-1 protein, they saw that the worms surprisingly developed an enhanced ability to pass on changes in gene expression to their offspring. In fact, these changes persisted for over 100 generations—even after the researchers returned SID-1 to the worms.
Potential implications for human medicine
“Interestingly, proteins similar to SID-1 can also be found in other animals, including humans,” added Jose. “Understanding SID-1 and its function could have significant implications for medicine. If we learn how this protein controls the transfer of RNA between cells, we may be able to develop more targeted treatments for human diseases, and perhaps even control the inheritance of certain disease conditions.”
The research team also identified a gene called sdg-1 that helps regulate “jumping genes” — DNA sequences that tend to move or replicate themselves to different places on a chromosome. Although “jumping genes” can sometimes cause beneficial genetic changes, they are more likely to disrupt existing sequences and cause disease. The researchers found that the sdg-1 gene is located within a “jumping gene” but produces proteins that are used to control the movement of the jumping genes, creating a self-regulatory loop that may prevent unwanted movements and changes.
“It’s fascinating to see how these cellular mechanisms maintain a delicate balance, similar to a thermostat that maintains the right temperature in a house, so that it’s not too hot or too cold,” Jose explained. “The system needs to be flexible enough to allow for some genetic ‘jumping’, but also to prevent excessive movement that could be harmful to the organism.”
Jose believes the team's findings provide important insights into how animals regulate their genes and maintain stable gene expression across generations. Studying these mechanisms could pave the way for innovative treatments for inherited diseases in humans.
Next, the team plans to investigate mechanisms related to the transfer of different types of dsRNA, where SID-1 is located, and why some genes are regulated across generations while others are not.
“We’re just getting started,” Jose said. “What we’ve discovered is just the tip of the iceberg in understanding how external RNA can cause heritable changes that persist over many generations. This research will help scientists better understand how to design and deliver RNA-based drugs to patients more effectively.”
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