CRISPR is best known for cutting and changing DNA. Now, researchers are using the technology in a different way: controlling whether genes are active without altering the genetic sequence itself.
Scientists from UNSW Sydney and St. Jude Children’s Research Hospital used a modified CRISPR system to remove DNA methylation from genes that produce fetal hemoglobin. Once the methyl groups were removed, the previously silenced genes switched back on. Adding the methyl groups again reduced their activity.
The findings show how CRISPR-based epigenetic editing could one day offer a new approach to treating inherited blood disorders such as sickle cell disease. They also provide evidence that DNA methylation can actively maintain gene silencing rather than simply appearing after a gene has already been turned off.
CRISPR Without Cutting DNA
Traditional CRISPR-Cas9 editing uses a guide RNA to direct the Cas9 enzyme to a specific location in the genome, where it cuts the DNA. Although this approach has transformed genetic research, the cell must repair the break, creating a risk of unintended changes.
Epigenetic editing works differently. Researchers use dCas9, a modified form of Cas9 that can locate a chosen DNA sequence but cannot cut it. Instead, it carries enzymes that add or remove epigenetic marks that affect gene activity.
In this study, dCas9 delivered part of the TET1 enzyme to the promoters of HBG1 and HBG2,two genes responsible for producing fetal hemoglobin. TET1 helped remove methyl groups from these regions without changing the DNA sequence.
Testing Whether Methylation Really Silences Genes
DNA methylation occurs when small chemical tags called methyl groups are added to DNA. When methylation accumulates near a gene’s promoter, it is commonly associated with reduced gene activity.
Scientists have long debated whether methylation directly causes silencing or merely builds up after a gene becomes inactive—like cobwebs collecting on a gene that has already been switched off. By removing and restoring methylation at the same promoters, the researchers could test cause and effect.
Targeted demethylation strongly activated the fetal globin genes in a human red blood cell precursor line. When methylation was added back, gene activity decreased again.
“We showed very clearly that if you brush the cobwebs off, the gene comes on,” said study lead Professor Merlin Crossley of UNSW Sydney. When the researchers added the methyl groups back, the genes switched off again, showing that the tags were not simply cobwebs but anchors holding the genes in a silenced state.
Why Fetal Hemoglobin Matters
Fetal hemoglobin is the main form of hemoglobin produced before birth. Around birth, the fetal globin genes are normally switched off as the body begins producing adult hemoglobin.
This transition is important in sickle cell disease, which is caused by a mutation affecting the beta-globin component of adult hemoglobin. The resulting abnormal hemoglobin can make red blood cells rigid and sickle-shaped, contributing to anemia, pain, blocked blood vessels, and organ damage.
Because fetal hemoglobin does not contain the affected beta-globin protein, switching it back on may help compensate for the defective adult form.
In blood-forming cells from healthy donors, the researchers reduced methylation at the fetal globin promoters from about 70% to around 10%. Fetal globin gene expression increased from roughly 7%–8% to approximately 35%.
What the Findings Could Mean
Avoiding DNA cuts may reduce some of the risks associated with conventional CRISPR editing, such as unwanted changes created during DNA repair. It could also allow researchers to adjust gene activity while leaving the genetic sequence intact.
Study co-author Professor Kate Quinlan said the approach could “boost gene expression without modifying the DNA sequence.”
The same basic technique might eventually be applied to other diseases involving genes that are incorrectly silenced or activated. Different CRISPR-based editors could potentially remove DNA methylation, add it, or alter other epigenetic signals.
However, avoiding DNA cuts does not automatically make the approach safe. Researchers will still need to study whether the editor affects unintended regions of the genome or causes unexpected changes in other genes.
The experiments were conducted in cultured human cells, so researchers still need to test the approach in animals and determine how stable the changes are inside the body. Even so, the study demonstrates how CRISPR may one day control epigenetic gene switches without changing the underlying DNA sequence.
Source: Bell, H.W., Feng, R., Shah, M., et al. Removal of promoter CpG methylation by epigenome editing reverses HBG silencing. Nature Communications. July 2025.
Reference: Lachlan Gilbert. New CRISPR technique could rewrite future of genetic disease treatment. University of New South Wales. August 14, 2025.
