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KAIST develops technology for selective RNA modification in living cells and animals · A team led by Professor Won Do Heo from the Department of Biological Sciences, KAIST, has developed a pioneering technology that selectively acetylates specific RNA molecules in living cells and tissues. · The platform uses RNA-targeting CRISPR tools in combination with RNA-modifying enzymes to chemically modify only the intended RNA. · The method opens new possibilities for gene therapy by enabling precise control of disease-related RNA without affecting the rest of the transcriptome. < Photo 1. (From left) Professor Won Do Heo and Jihwan Yu, a Ph.D. Candidate of the Department of Biological Sciences > CRISPR-Cas13, a powerful RNA-targeting technology is gaining increasing attention as a next-generation gene therapy platform due to its precision and reduced side effects. Utilizing this system, researchers at KAIST have now developed the world’s first technology capable of selectively acetylating (chemically modifying) specific RNA molecules among countless transcripts within living cells. This breakthrough enables precise, programmable control of RNA function and is expected to open new avenues in RNA-based therapeutic development. KAIST (President Kwang Hyung Lee) announced that a research team led by Professor Won Do Heo in the Department of Biological Sciences has recently developed a groundbreaking technology capable of selectively acetylating specific RNA molecules within the human body using the CRISPR-Cas13 system—an RNA-targeting platform gaining increasing attention in the fields of gene regulation and RNA-based therapeutics. RNA molecules can undergo chemical modifications—the addition of specific chemical groups—which alter their function and behavior without changing the underlying nucleotide sequence. However, some of these modifications, a critical layer of post-transcriptional gene regulation, remain poorly understood. Among them, N4-acetylcytidine (ac4C) has been particularly enigmatic, with ongoing debate about its existence and function in human messenger RNA (mRNA), the RNA that encodes proteins. To address this gap, the KAIST research team developed a targeted RNA acetylation system, named dCas13-eNAT10. This platform combines a catalytically inactive Cas13 enzyme (dCas13) that guides the system to specific RNA targets, with a hyperactive variant of the NAT10 enzyme (eNAT10), which performs RNA acetylation. This approach enables precise acetylation of only the desired RNA molecules among the vast pool of transcripts within the cell. < 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. > Using this system, the researchers demonstrated that guide RNAs could direct the dCas13-eNAT10 complex to acetylate specific RNA targets, and acetylation significantly increased protein expression from the modified mRNA. Moreover, the study revealed, for the first time, that RNA acetylation plays a role in intracellular RNA localization, facilitating the export of RNA from the nucleus to the cytoplasm—a critical step in gene expression regulation. To validate its therapeutic potential, the team successfully delivered the targeted RNA acetylation system into the livers of live mice using adeno-associated virus (AAV), a commonly used gene therapy vector. This marks the first demonstration of in vivo RNA modification, extending the applicability of RNA chemical modification tools from cell culture models to living organisms. < 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, with Ph.D. candidate Jihwan Yu from the Department of Biological Sciences at KAIST as the first author, was published in the journal Nature Chemical Biology on June 2, 2025. (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.
2025.06.10 View 6730