• Professor Won Do Heo's team in the Department of Biological Sciences develops targeted RNA modification technology, the world's first to acetylate (chemically modify) desired RNA within cells and living animal tissues using RNA gene scissors and RNA chemical modification enzymes.
• Expectation for future application in gene therapy technology as only desired RNA can be controlled.
< Photo 1. (From left) Professor Won Do Heo, Department of Biological Sciences, Jihwan Yu, Ph.D. Candidate >
RNA gene scissors (CRISPR-Cas13) are gaining significant attention as a next-generation gene therapy with fewer side effects. They can suppress infection by eliminating viral RNA, such as in coronaviruses, or regulate the expression of disease-causing genes. KAIST researchers have developed the world's first technology that can precisely locate and acetylate (chemically modify) only the desired RNA among countless RNA molecules (molecules crucial for transmitting genetic information and producing proteins) within cells. This is expected to be a key technology that could open a new chapter in RNA-based therapies.
KAIST (President Kwang Hyung Lee) announced on the 10th that Professor Won Do Heo's research team in the Department of Biological Sciences has recently developed an innovative technology capable of acetylating specific RNA in the human body using the CRISPR-Cas13 system, an RNA gene scissors system gaining attention in the field of gene regulation and RNA-based technology.
RNA can undergo changes in its properties and functions through a process called 'chemical modification'. Chemical modification is a gene regulation process where specific chemical groups are added, altering the properties and roles of RNA without changing its nucleotide sequence. One such chemical modification is cytidine acetylation (N4-acetylcytidine). Until now, the precise function of this chemical modification within cells has not been clearly understood. In particular, there has been ongoing debate about whether this modification truly exists in human mRNA (RNA that produces proteins) and what role it plays.
To overcome these limitations, the research team developed a 'targeted RNA acetylation system (dCas13-eNAT10)' by combining Cas13, a gene scissors that precisely targets desired RNA, with a hyperactive variant of NAT10 (eNAT10), an enzyme that acetylates RNA. In essence, they created a 'targeted RNA modification technology' that precisely selects and acetylates only the desired RNA.
< Figure 1. Development of hyperactive variant eNAT10 through NAT10 protein engineering. By engineering the NAT10 protein, which performs RNA acetylation in human cells, based on its domain and structure, eNAT10 was developed, showing approximately a 3-fold increase in RNA acetylation activity compared to the wild-type enzyme. >
The research team demonstrated that the targeted RNA acetylation system, guided by guide RNA that locates specific RNA within cells, can introduce acetylation chemical modifications to desired RNA. Through this, they confirmed that protein production increases in messenger RNA (mRNA) that has undergone acetylation chemical modification.
Furthermore, the research team, using the developed system, revealed for the first time that RNA acetylation facilitates the translocation of RNA from the cell nucleus to the cytoplasm. This study demonstrates the possibility that acetylation chemical modification can also regulate intracellular RNA 'localization'.
The research team also proved that the developed technology could precisely control RNA acetylation within an animal's body by delivering the targeted RNA acetylation system to the liver of experimental mice via AAV (adeno-associated virus), a widely used viral vector in gene therapy. This is the first case to show that RNA chemical modification technology can be extended to in vivo applications. This achievement is evaluated as opening up possibilities for application in RNA-based gene therapy technology.
< Figure 2. Acetylation of various RNA in cells using dCas13-eNAT10 fusion protein. Utilizing the CRISPR-Cas13 system, which can precisely target specific RNA through guide RNA, a dCas13-eNAT10 fusion protein was created, demonstrating its ability to specifically acetylate various endogenous RNA at different locations within cells. >
Professor Won Do Heo, who previously developed COVID-19 treatment technology using RNA gene scissors and technology to activate RNA gene scissors with light, stated, "Existing RNA chemical modification research faced difficulties in controlling specificity, temporality, and spatiality. However, this new technology allows selective acetylation of desired RNA, opening the door for accurate and detailed research into the functions of RNA acetylation." He added, "The RNA chemical modification technology developed in this study can be widely used as an RNA-based therapeutic agent and a tool for regulating RNA functions in living organisms in the future."
< Figure 3. In vivo delivery of targeted RNA acetylation system. The targeted RNA acetylation system was encoded in an AAV vector, commonly used in gene therapy, and delivered intravenously to adult mice, showing that target RNA in liver tissue was specifically acetylated according to the guide RNA. >
This research, in which Jihwan Yu, a Ph.D. candidate in the Department of Biological Sciences at KAIST, served as the first author, was published in the international journal 'Nature Chemical Biology' on June 2, 2025. (Paper Title: Programmable RNA acetylation with CRISPR-Cas13, Impact factor: 12.9, DOI: https://doi.org/10.1038/s41589-025-01922-3)
This research was supported by the Samsung Future Technology Foundation and the Bio & Medical Technology Development Program of the National Research Foundation of Korea.
