Genetic engineering concept. DNA. Gene therapy. Medical technology
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Scientists at Hokkaido University in Japan have discovered that a small RNA molecule, called 4.5SH, found exclusively in small rodents such as mice and rats, may act as a pivotal player in gene expression regulation and represent the first of a novel class of regulatory RNAs.

RNA, or ribonucleic acid, has long been acknowledged for its role as the courier of genetic information in the form of mRNA. However, beyond this, RNA operates in various capacities, including the regulation of gene activity through small non-coding RNAs— genetic sequences that do not contribute to protein generation.

Reporting in Molecular Cell, researchers have delved into the depths of 4.5SH RNA to uncover its previously unknown function. Discovered in the 1970s, 4.5SH RNA has been found in abundance across diverse tissues, yet its purpose remained unknown for over four decades.

This small RNA, synthesized from multiple copies of its gene, results in the accumulation of up to an astounding 10,000 copies per cell. Through meticulous experimentation and genetic manipulation in mouse embryos, the team discovered that the absence of 4.5SH led to early embryo-stage deaths. Intriguingly, this highlighted the RNA’s role as a natural gene therapy system, acting as a safeguard against lethal mutations in essential protein-coding genes within the mouse genome.

“4.5SH RNA has the ability to detoxify these mutations in bulk—essentially, it is a natural gene therapy to protect against mutations,” explained Shinichi Nakagawa, professor at Hokkaido University and lead author of the study.

Further investigation into the structure of 4.5SH RNA uncovered a two-module composition. According to the researchers, one module functions as a sensor, identifying abnormal genetic sequences, while the other module acts as a tool, preventing the incorporation of these abnormal sequences into mRNA through a process known as alternative splicing.

“To our knowledge, this is the first example of a naturally produced RNA that can regulate alternative splicing in a definitive on/off manner,” Nakagawa explained. The implications extend beyond the specific RNA, suggesting that a considerable portion of non-coding RNAs may partake in controlling alternative splicing, a critical aspect of gene regulation.

In an intriguing twist, the researchers used 4.5SH to engineer a programmable molecular system capable of manipulating splicing in selected ways. The scientists believe that this breakthrough presents a potential new tool for genetic engineering, offering opportunities to precisely tailor gene expression.

Nakagawa envisions the practical applications of this discovery, stating, “Our discovery suggests the possibility of developing new gene therapy drugs that recognize only specific genetic mutations by modifying the sensor module of 4.5SH RNA, so we may be able to prevent toxic regions associated with disease from being expressed.”

This revelation not only sheds light on the long-standing mystery of 4.5SH RNA but also opens avenues for future research into the therapeutic applications of this natural gene therapy system, paving the way for innovative approaches in genetic medicine.

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