Researchers Discover Essential Processes in Gene Regulation That Could Enhance RNA Drug Development
RNA-based therapies hold immense potential for combating various diseases, as seen in the recent effectiveness of RNA vaccines and double-stranded RNA (dsRNA) treatments. Despite successful advancements in creating drugs that leverage dsRNA to specifically target harmful genes, a significant obstacle still exists: efficiently delivering these vital RNA molecules into cells.
A recent study published in the journal eLife on February 4, 2025, may pave the way for significant advancements in RNA drug development. Researchers from the University of Maryland used microscopic roundworms to explore how dsRNA molecules naturally penetrate cells and affect future generations. Their work unveiled several routes through which dsRNA enters the roundworms’ cells, promising to enhance drug delivery techniques in humans.
“Our research challenges earlier views on RNA transport,” explained Antony Jose, the senior author and an associate professor in cell biology and molecular genetics at UMD. “We found that RNA can convey specific messages not just between cells but also across numerous generations, providing a fresh perspective on the mechanisms of inheritance.”
The research team identified a protein named SID-1, which functions as a gatekeeper for dsRNA information transfer. They discovered that SID-1 also plays a role in gene regulation across generations. Removal of SID-1 caused the roundworms to become unexpectedly proficient at transmitting changes in gene expression to their descendants, with these changes lasting more than 100 generations—even after reinstating SID-1 in the worms.
“Interestingly, similar proteins to SID-1 are present in other species, including humans,” noted Jose. “Understanding SID-1’s function is crucial for human health. If we can grasp how this protein manages RNA communication between cells, we might develop more targeted treatments for diseases and potentially control the inheritance of specific health conditions.”
The investigators also identified a gene called sdg-1, which is involved in regulating ‘jumping genes’—DNA segments that move or replicate themselves across different chromosomal locations. Although jumping genes can create advantageous genetic diversity, they often disrupt existing gene sequences, leading to diseases. The research revealed that sdg-1 resides within a jumping gene but produces proteins to help control these jumping genes, forming a self-regulating system that could curb undesirable gene movements and mutations.
“It’s remarkable how these cellular systems keep a delicate equilibrium, similar to a thermostat that maintains a comfortable home temperature,” Jose elaborated. “The system must be adaptable enough to allow some jumping activity while curbing excessive movements that could endanger the organism.”
Jose asserts that these findings shed light on how animals manage their gene expression and maintain stability across generations. Investigating these regulatory processes might ultimately lead to innovative treatments for hereditary diseases in humans.
Looking forward, the team aims to further explore the mechanisms involved in the transport of various forms of dsRNA, the location of SID-1, and why some genes are regulated across generations while others are not.
“We’re only beginning to uncover these systems,” Jose remarked. “What we’ve found is just the starting point for understanding how external RNA can induce heritable changes that endure for generations. This research will aid scientists in devising and effectively delivering RNA-based treatments to patients.”
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The research paper titled “Intergenerational transport of double-stranded RNA in C. elegans can limit heritable epigenetic changes,” was published in the journal eLife on February 4, 2025.
Besides senior author Antony Jose and lead author Nathan Shugarts (Ph.D. ’21, biological sciences), additional UMD co-authors include Aishwarya Sathya, a biological sciences Ph.D. student, Andrew L. Yi (B.S. ’19, biological sciences; B.S. ’22, psychology), Winnie M. Chan (B.S. ’19, biological sciences; B.S. ’22, psychology), and Julia A. Marré (B.S. ’09, Ph.D. ’17, biological sciences).
This study was funded by the National Institutes of Health (Award Nos. R01GM111457 and R01GM124356) and the U.S. National Science Foundation (Award No. 2120895). The opinions expressed in this article do not necessarily reflect those of these organizations.
