GoKawiilEpigenetic modifications to DNA (yellow), such as those catalysed by DNA methyltransferase enzymes (blue, centre) control gene expression.Credit: Juan Gaertner/Science Photo Library
Marianne Rots first started talking about epigenome editing on the conference circuit about two decades ago. If natural epigenetic marks such as DNA methylation and histone acetylation control gene expression, she reasoned, then artificially modifying those marks should allow scientists to adjust that expression. But many of her peers scoffed, assuming that epigenetic tags could not trigger such changes. “We really had to fight dogmas, that people thought, this will never, ever work,” says Rots, an epigeneticist at the University Medical Center Groningen in the Netherlands.
Then came the CRISPR–Cas system. Although the technology first made a splash in gene editing, scientists such as Rots now use it to precisely target epigenetic editors to any DNA sequence. Suddenly, epigenetics researchers could not only silence or activate genes, but also dial gene expression up or down. More than a dozen companies are now exploring epigenetic-editing technology, and a handful of early-stage clinical trials are under way.
Tunable and flexible, epigenetic editing stands in elegant contrast to gene editing. CRISPR’s Cas enzyme slashes genetic material apart, then relies on cellular systems to repair it, hopefully incorporating the desired edit. Epigenetic editing is gentler, leaving the DNA strands and code unchanged, and can induce either temporary or permanent changes.
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“I find epigenome editing to be much more sophisticated, much more complex,” says Charles Gersbach, a biomedical engineer at Duke University in Durham, North Carolina. “There are just so many more things that you can do with epigenome editing that aren’t necessarily doable with genome editing.”
For example, in epigenetic editing, adding a handful of guide RNAs — the nucleic acids that target the Cas enzyme to a specific genomic location — to the machinery allows scientists to alter several sites at once. By contrast, because gene editing requires creating a double-stranded DNA break, editing several gene sequences at once risks the pieces reconnecting in unnatural, dangerous configurations.
Researchers are using epigenetic editing to explore the intricacies of gene expression and to develop therapies. Plant scientists are fiddling with epigenomes, too, to create crop variants that differ not in DNA sequence, but in gene activity. But the epigenome is complex, and many projects require trial and error.
“We really don’t understand the rules,” says Rots. “We cannot predict the final outcome of our biological experiments.”
From the bench …
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