A team of researchers at MIT’s McGovern Institute for Brain Research and the Broad Institute of MIT and Harvard
has uncovered an ancient RNA-guided system that could expand the current genome editing toolkit. This discovery, published in Science on February 27, introduces a system called TIGR (Tandem Interspaced Guide RNA) that uses RNA to target specific sites on DNA.
Highly Modular and Programmable: TIGR systems can be reprogrammed to target any DNA sequence, making them highly flexible.
More Compact Than CRISPR: Compared to existing RNA-guided tools like CRISPR, TIGR systems are significantly smaller, making them easier to deliver in therapeutic applications.
No Dependence on PAM Sequences: Unlike CRISPR systems, which require short PAM (Protospacer Adjacent Motif) sequences for targeting, TIGR systems have no such constraint, allowing them to edit any location in the genome.
Higher Precision: TIGR systems use a dual-guide mechanism, interacting with both strands of the DNA double helix, which enhances targeting accuracy and reduces the risk of unintended modifications.
Led by Feng Zhang, a pioneer in gene-editing research, the team began by searching for proteins that share structural similarities with Cas9, the key enzyme in CRISPR-based genome editing. Using AI-driven deep mining techniques, they scanned hundreds of millions of known and predicted protein structures, searching for those that had RNA-binding properties.
Their search eventually led them to TIGR-Tas proteins, which were found in over 20,000 different variants, primarily in viruses that infect bacteria. These proteins interact with RNA guides encoded by TIGR arrays within their genes, enabling targeted DNA modifications. Some Tas proteins have built-in DNA-cutting domains, while others appear to interact with additional proteins that could assist in directing edits to specific genomic sites.
Human Gene Editing: Some TIGR-Tas proteins have already been successfully programmed to make precise cuts in human DNA, demonstrating their potential for gene-editing therapies.
More Efficient Therapeutic Delivery: The smaller size of TIGR proteins could help overcome one of the biggest challenges in gene therapy—efficient delivery into human cells.
Understanding Cellular Mechanisms: The team also noted intriguing connections between TIGR-Tas systems and RNA-processing proteins in human cells, suggesting possible insights into natural biological processes.
Conclusion
The discovery of TIGR-Tas systems represents a major advancement in genome editing. With their compact size, flexibility, and precise targeting ability, they could become a powerful alternative to existing gene-editing tools like CRISPR. The research team is now working to further optimize these systems for research and therapeutic use.
This work was supported by the Helen Hay Whitney Foundation, Howard Hughes Medical Institute, K. Lisa Yang and Hock E. Tan Center for Molecular Therapeutics, Broad Institute Programmable Therapeutics Gift Donors, Pershing Square Foundation, William Ackman, Neri Oxman, the Phillips family, J. and P. Poitras, and the BT Charitable Foundation.
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