Ancient RNA-Guiding System Identified, Expanding Genome Editing Possibilities

Scientists at MIT and Harvard have uncovered a new class of DNA-targeting systems called TIGR (Tandem Interspaced Guide RNA), which could potentially expand the genome editing toolbox. These compact, RNA-guided systems, found primarily in bacteria-infecting viruses, offer unique advantages over existing tools like CRISPR.

The research team, led by Feng Zhang, identified over 20,000 different TIGR-associated (Tas) proteins. These proteins share a characteristic RNA-binding component that interacts with an RNA guide, directing it to specific DNA sites. Some Tas proteins can cut DNA at targeted locations, while others appear to bind to other proteins, potentially guiding them to DNA targets.

TIGR systems boast several key features that set them apart from current genome editing tools. Their modularity allows for distinct functional modules to act on targeted DNA. Their compact size, significantly smaller than CRISPR systems, facilitates easier delivery for therapeutic applications. Unlike CRISPR, TIGR systems do not require specific adjacent motifs (PAMs) to target DNA sequences, offering greater flexibility. Additionally, a "dual-guide system" interacts with both DNA strands, potentially ensuring greater specificity.

"This is a very versatile RNA-guided system with a lot of diverse functionalities," says Zhang, senior author on the paper published in Science. The team demonstrated that some Tas proteins could be programmed to make targeted cuts in human cell DNA.

The discovery process involved an extensive search of biological proteins, utilizing artificial intelligence to analyze and cluster the results. The researchers are now investigating the natural role of TIGR systems in viruses and exploring their potential adaptations for research and therapeutics. They have determined the molecular structure of one of the Tas proteins they found to work in human cells, and will use that information to guide their efforts to make it more efficient. Additionally, they note connections between TIGR-Tas systems and certain RNA-processing proteins in human cells. “I think there’s more there to study in terms of what some of those relationships may be, and it may help us better understand how these systems are used in humans,” Zhang says.