Scientists Develop CRISPRoff for Controlling Gene Expression through Heritable Epigenetic Memory

This seems like it will be pretty damn important in the future.

Scientists led by a team at the Whitehead Institute have developed a new gene editing technology, called CRISPRoff, which can be used to control gene expression with high specificity, while leaving the sequence of the DNA unchanged.

the method is also fully reversible.

(There’s a CRISPRon too.)

“The big story here is we now have a simple tool that can silence the vast majority of genes,” said Weissman, who is also a professor of biology at MIT and an investigator with the Howard Hughes Medical Institute. “We can do this for multiple genes at the same time without any DNA damage, with great deal of homogeneity, and in a way that can be reversed. It’s a great tool for controlling gene expression.”

“An alternative modality for modulating gene function is to rewrite the epigenetic landscape to control gene expression without changing the underlying DNA sequence,” they wrote. This epigenetic strategy is designed to silence or activate genes based on chemical changes to the DNA strand.

To build an epigenetic editor that could mimic natural DNA methylation, the researchers created a tiny protein machine that, guided by small RNAs, can tack methyl groups onto specific spots on the strand. These methylated genes are then silenced, or turned off, hence the name CRISPRoff. Because the method does not alter the sequence of the DNA strand, the researchers can reverse the silencing effect through the use of enzymes that remove the methyl groups, a method that they called CRISPRon.

As they tested CRISPRoff in different conditions, the researchers discovered that they could target the method to the vast majority of genes in the human genome, and that also it worked not just for the genes themselves, but for other regions of DNA that control gene expression but do not code for proteins. “Our initial experiments demonstrate CRISPRoff can perturb enhancers, opening the potential to target genome elements that control tissue-specific gene expression.” First author Nuñez acknowledged, “That was a huge shock even for us, because we thought it was only going to be applicable for a subset of genes.”

It just keeps sounding better and better.

And while delivery to specific tissues remains a challenge for gene editing technologies such as CRISPRoff, as Weissman noted, “we showed that you can deliver it transiently as a DNA or as an RNA, the same technology that’s the basis of the Moderna and BioNTech coronavirus vaccine.”