CRISPR ‘tweezers’ relocate genes to change their function

The CRISPR-Cas9 system is often compared to scissors, because the technology cuts out segments of DNA. Researchers at Stanford University have designed a new CRISPR gene-editing tool that they say is more like molecular “tweezers,” and they believe the invention might someday be used in treating diseases like cancer.

The new technique, called CRISPR-genome organization, or CRISPR-GO, allows scientists to reorganize the genome in three dimensions—taking specific genetic pieces and placing them at different locations in a cell’s nucleus, the Stanford team explained in a study published in Cell.

Unlike the “cutting” mechanism of CRISPR-Cas9, CRISPR-GO uses a programmable guide RNA to deliver small parts of DNA to a new location in the nucleus. It involves three parts, explained Stanley Qi, the study’s senior author, in a statement.

First is the “address” of the genetic target, to which a complementary RNA will bind. Then there's the new address, namely another portion of DNA where the chromatin will be relocated. Then a catalyst is needed to solidify this piece of DNA at its new site.

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The nucleus has multiple compartments that play different roles in cell functionality. For example, "Cajal bodies" are amorphic regions that are enriched in proteins and RNAs. Using CRISPR-GO, the team found that genes relocated to this part of the nucleus stopped expressing proteins.

“[I]t's the first time that researchers have evidence to show the Cajal body can have a direct gene-regulation effect, in this case repressing gene expression,” Qi said in the statement. “It suggests that the Cajal body has some unexpected role in controlling transcription.”

This could make CRISPR-GO useful in oncology. Qi plans to move a promyelocytic leukemia (PML) body next to cancer-causing genes in the nucleus. PML protein is known for its tumor-suppressing function, so Qi wants to see if pulling pro-tumor genes closer to it can curb tumor formation.

Qi and his team are not alone in seeking new ways to optimize the all-powerful CRISPR technology. Beam Therapeutics, a 2018 Fierce 15 winner co-founded by CRISPR moguls Feng Zhang and David R. Liu, is developing a base-editing platform. Rather than cutting the genome, Beam’s CRISPR operates more like a pencil, editing one nucleotide base without disrupting the sequence.

Two separate recent studies in the journal Nature Medicine used modified versions of CRISPR-Cas9 to target genetic liver diseases. One team from the University of Pennsylvania adopted a base editor 3 system to carry an enzyme that corrected a genetic sequence in fetal mice. Another team at ETH Zurich added an enzyme called cytidine deaminase to CRISPR-Cas9 and successfully converted a DNA fragment that causes a metabolic disorder called phyenylketonuria in adult mice.

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CRISPR-GO could find many uses beyond oncology, Qi's team believes. Traditional technologies allow scientists to look at the physical structure of cells and determine where DNA resides in the nucleus. But what they don’t show is how changing a specific genetic element's location will affect its function. With CRISPR-GO, researchers can move those elements around to test various hypotheses.

Although there's more work to be done to perfect the technology, Qi believes the ability to explain specific location-based effects in different nuclear compartments will boost future studies in human health. 

"We're very excited about the potential here and, while we've answered a couple questions, we've opened up about 20 more," Qi said.