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CRISPR Epigenetic Editing Silences Genes Without DNA Edits

27 April 2021
Giulio Prisco

DNA Editing

Scientists at UC San Francisco and Whitehead Institute have modified CRISPR cut-and-paste gene editing technology to extend its reach beyond genome editing and into epigenomic editing. The epigenome is the set of proteins and small molecules that control gene expression and gene activation. In other words, it controls when and where target genes are switched on or off.

In a research paper published in Cell, the scientists describe a new CRISPR-based tool called “CRISPRoff.” It permits switching off almost any gene in human cells without making a single edit to the genetic code. The scientists also show that once a gene is switched off, it remains inert in the cell’s descendants for hundreds of generations. And it can be switched back on with a complementary epigenetic modification tool called “CRISPRon,” also described in the paper.

“The big story here is we now have a simple tool that can silence the vast majority of genes,” says research co-leader Jonathan Weissman in a press release issued by Whitehead 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.”

By switching genes on and off, the epigenome plays a central role in many diseases, from viral infection to cancer. Therefore, CRISPRoff technology may one day lead to powerful epigenetic therapies for these diseases. And because this approach doesn’t involve any DNA sequence edits, it’s likely to be safer than conventional CRISPR-mediated therapeutics. Conventional CRISPR has been known to cause unwanted and potentially harmful changes to the genome.

“Though genetic and cellular therapies are the future of medicine, there are potential safety concerns around permanently changing the genome, which is why we’re trying to come up with other ways to use CRISPR to treat disease,” says research co-leader Luke Gilbert in a press release issued by UC San Francisco.

CRISPRoff allows expressing a protein briefly “to write a program that's remembered and carried out indefinitely by the cell,” adds Gilbert. “It changes the game so now you're basically writing a change that is passed down through cell divisions - in some ways we can learn to create a version 2.0 of CRISPR-Cas9 that is safer and just as effective.”

As an example of how this epigenetic regulation might be applied to therapeutics, the scientists show that CRISPRoff could be used to turn down (although not entirely off) the expression of the gene that codes for Tau protein. This protein is implicated in Alzheimer’s disease.

How to deliver CRISPRoff therapeutics to Alzheimer’s patients, and more generally how to deliver it to specific tissues, is a challenge that future research will need to address. But, Weissman says, “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.”

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