New CRISPR gene switch – CRISPRoff

Published in Cell on Apr 9, 2021 is a new paper that describes a huge leap forward for CRISPR. This is perhaps the biggest CRISPR advance since 2013.

Titled “Genome-wide programmable transcriptional memory by CRISPR-based epigenome editing”, the paper has the following four highlights …

  • CRISPRoff is a single fusion protein that programs heritable epigenetic memory
  • CRISPRoff can heritably silence most genes, including genes without CpG islands
  • CRISPRoff is highly specific and has a broad targeting window across gene promoters
  • CRISPRoff epigenetic memory persists through differentiation of iPSCs into neurons

What does this actually mean?

In essence, what we have here is a way to use CRISPR as an on-off switch for genes.

Yes, they have both a CRISPRoff and also a CRISPRon.

Let’s take this step by step.

I’m going to keep this really short.

CRISPR is an acronym for clustered regularly interspaced short palindromic repeats. DNA contains these.

There exists a protein called Cas9 (or “CRISPR-associated protein 9”). The beauty of Cas9 is that it naturally can seek out a specific CRISPR sequence and then cut the DNA at that point. To translate that: you have in effect got, via CRISPR-Cas9 a tool that you can use to edit DNA.

What this new system does is that it targets a specific gene as usual but then, instead of cutting the DNA, it methylates the gene – adding methyl groups to some of the base pairs. This basically turns the gene off. This is because doing this prevents the transcriptase enzyme from worked on the DNA at that location. The sequence is still there, it is essentially locked and unavailable.

What is fascinating is that this methylation stays and persist within subsequence generations. In other words, it is not just a temporary hack.

What is also interesting is that this appears to be very generic and works on most genes. That makes this a very powerful tool.

Having got a tool to apply the methylation they also came up with a way to strip it away. They call this CRISPRon.

So overall this enables them to both turn genes off and on.


Once you can do that, you can start switching off and then back on specific genes to see what they actually do. That makes this a new immensely powerful research tool.

Beyond just research, this could also be a new treatment that will be used to potentially target specific genes. That however is still a lot further away, the big tick-in-the-box right now is that it is a new research tool.

Botton line: This really is a very big deal.

Tweets – CRISPRoff

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