Inside our cells, DNA does not lie flat like a line of text—it folds, twists, and loops into complex 3D shapes, all tightly packed inside the tiny space of the nucleus. Part of this folding happens as DNA wraps around proteins called histones, like thread winding around spools. Scientists already know that when the 3D shape of biomolecules like proteins or RNA changes, it dramatically affects their function. Similarly, changing how tightly DNA coils around histones has been shown to switch genes on or off. But what happens if we go a step further, if we deliberately change the way DNA folds in 3D space? Not just a small portion, but the physical structure of the genome itself, including numerous genes and complexes that support various biological processes. Could that change how the cell behaves?

In a recent study published in eLife, scientists at the CSIR-Institute of Genomics and Integrative Biology (IGIB) altered the folding of a small section of the packaged DNA inside human cells. They found that a small 3D structural change is enough to switch on distant genes and reorganise the local layout of the genome.

To make these new folds, the researchers used a special structure called a G-quadruplex, or G4. DNA is made up of four chemical bases: adenine (A), thymine (T), cytosine (C), and guanine (G). In certain regions where guanine repeats, the DNA strand can loop back on itself and form a G4 structure. These structures can loosen up the surrounding DNA packaging, making it easier for genes to turn on. G4 structures occur naturally in our genome, and are often observed near active genes. "We already know that G4 structures act as landmarks, helping the gene-activating proteins recognise where their target gene is. But whether they could affect genes far away from their location was still unknown. And no one really knew what would happen if an array of G4s was added to or removed from the genome," says Shuvra Shekhar Roy, a former PhD student at IGIB, and the lead author of the study.

The research team inserted a short, guanine-rich DNA sequence into a neutral region of the genome. This region had no active genes, no natural G4s, and was not involved in any significant 3D folding, making it the perfect place to test whether the G-quadruplex structure alone could trigger changes.

As soon as the guanine-rich DNA folded into G4s, this quiet stretch suddenly lit up. Molecular tags that are usually found at active gene control regions appeared, and key proteins involved in switching genes on gathered at the site. "These tags include chemical marks and protein modifications that are known to activate many genes across the genome," said Roy.

But the story doesn't end there. The G4s made an impact on regions beyond the nearby DNA. Using a technique called Hi-C, which maps how DNA folds and interacts in 3D space, the researchers found that the G4 had started forming new loops that connected it to genes far away—some as distant as five million base pairs. These genes, which had previously been inactive, had now switched on. To confirm that this effect was not unique to one region, the scientists repeated the experiment at a different location in the genome and found similar results. A tiny twist in DNA was enough to flip distant gene switches.

To make sure it was the G4's folded shape causing these changes, and not just the presence of a new DNA sequence, the team used special molecules called LNA probes to unfold the G4. When they did this, the activity faded: the molecular tags disappeared, and the previously activated genes went quiet again. This confirmed that it was the G-quadruplex's structure, not just its code, that was driving the changes in gene expression and genome architecture.

"Now that we know G4 loops can influence genes from a distance, there is a possibility that some diseases exist because these loops form where they should not – or are missing where they should be," said Roy. "If that is the case, G4s could be promising targets for correcting gene activity and treating such conditions," he added.

A tiny twist like a G4 loop might seem small, but if it can switch genes on or off, it could just as easily change how a cell behaves— because at its core, a cell is defined by which genes are active and when.