Researchers at UNSW Sydney and St. Jude Children’s Research Hospital report a CRISPR-derived “epigenome editing” approach that turns genes on by removing DNA methylation marks rather than cutting DNA. In cell-based experiments, they show that promoter methylation can directly—and reversibly—silence fetal globin genes, a finding they say helps settle a long-running debate about whether methylation is causal or merely correlated with gene shutdown. The work points to a potential path toward safer therapies for sickle cell disease by reactivating fetal hemoglobin without creating DNA breaks.
Researchers at UNSW Sydney, working with colleagues at St. Jude Children’s Research Hospital in Memphis, have demonstrated a CRISPR-based method for switching genes on and off by editing chemical marks on DNA instead of cutting the DNA itself.
The findings, published in Nature Communications, focus on DNA methylation—small chemical groups added to DNA that are often found at genes that are switched off. Using a modified CRISPR system designed to target these marks, the researchers report that removing methyl groups from gene promoters can reactivate gene expression in human cells grown in the lab. When methyl groups were restored at the same sites, the genes were silenced again.
“We showed very clearly that if you brush the cobwebs off, the gene comes on,” said study lead author Merlin Crossley, UNSW Deputy Vice-Chancellor Academic Quality. “And when we added the methyl groups back to the genes, they turned off again. So, these compounds aren’t cobwebs—they’re anchors.”
The researchers say the results support the view that methylation at promoters can play a direct, reversible role in gene repression, rather than merely appearing as a passive marker of already-inactive DNA.
A key disease-related target in the study is the fetal globin genes (HBG1/HBG2), which are normally silenced around the time of birth. Reactivating fetal hemoglobin is a well-established strategy for easing symptoms in disorders caused by defects in adult hemoglobin, including sickle cell disease. The new work suggests fetal globin could be reactivated through targeted promoter demethylation without introducing DNA double-strand breaks.
“Whenever you cut DNA, there’s a risk of cancer,” Crossley said, arguing that approaches that avoid cutting may reduce some safety concerns associated with nuclease-based genome editing.
Study co-author Kate Quinlan said the work illustrates a broader promise for “epigenetic” or “epigenome” editing. “We are excited about the future of epigenetic editing as our study shows that it allows us to boost gene expression without modifying the DNA sequence,” she said, adding that therapies built on this approach could have fewer unintended negative effects than earlier CRISPR strategies.
In a potential future clinical workflow described by the researchers, doctors could collect a patient’s blood stem cells, apply epigenome editing in the lab to remove methylation marks at the fetal globin gene promoters, and then return those cells to the patient to support production of healthier red blood cells.
So far, the work has been conducted in laboratory experiments using human cells. The teams say their next steps include testing the approach in animal models and expanding the toolkit of gene-targeted epigenetic modifications for therapeutic—and potentially agricultural—applications.
