What happens if you radically shuffle the layout of DNA? Much like rearranging the furniture in your home, you might discover that some elements work best only in very specific spots. Researchers from the lab of Oncode Investigator Bas van Steensel (Netherlands Cancer Institute) have now shown that one gene, Sox2, makes sure its favorite “helper” stays close - and doesn’t lend its support to other genes. This research is now published in Science.
Sox2 is a master regulator in embryonic stem cells. To stay active, it relies on an enhancer, a powerful stretch of DNA that acts like a cheerleader, boosting the gene’s activity from 100,000 letters away. But how does this enhancer stay loyal to Sox2, instead of cheering for other genes nearby?
Jumping DNA to Find the Rules
To answer this, the team used the Sleeping Beauty transposon, a mobile piece of DNA. With it, they attached a glowing reporter to a promoter and let it “hop” thousands of times across the Sox2 neighborhood. Depending on where the promoter landed, the enhancer either boosted its activity - or ignored it.
By measuring the glow, the researchers created a functional map of the region, showing exactly where the enhancer could switch on promoters.
A Narrow Zone of Influence
The results were clear: the enhancer’s pep talks were confined to a tight zone - the stretch of DNA between Sox2 and the enhancer itself. Within that zone, activity was strongest near the gene and the enhancer, matching known DNA loops that bring them close together in 3D.
Outside this boundary, the enhancer was silent. It did not activate other promoters, even if they were nearby.
“We thought a gene would always work better if it was closer to its enhancer, but that’s not the case. The neighborhood matters just as much,” says Oncode Researcher and PhD student Mathias Eder.
When the scientists removed Sox2, however, the enhancer’s influence spread much further. Promoters all across the region lit up. This revealed that Sox2 itself acts as a gatekeeper, keeping the enhancer’s power focused mainly on its own promoter.
The Hidden Booster Inside Sox2
How does Sox2 manage this? The team found the secret in its coding sequence - a chunk of DNA about 1,000 letters long. Surprisingly, this piece behaves a bit like a mini-enhancer. When the researchers added it to their reporter, it gave the promoter a strong competitive boost, helping it attract the enhancer’s attention.
This means Sox2 isn’t just a passive target. It carries its own built-in booster that helps secure the enhancer’s loyalty.
Scientific Impact
These findings change how we think about gene regulation. Enhancers may be powerful, but genes themselves can help compete for and confine their influence. Coding DNA - once considered only as instructions for proteins - can also shape how genes interact with enhancers.
The study is part of a broader effort at the Netherlands Cancer Institute to understand the “rules of the genome.” With new scrambling techniques, researchers can now flip, cut, and move large pieces of DNA to explore how position and neighborhood affect activity.
By showing how Sox2 keeps its cheerleader close, the researchers highlight the sophistication of genome architecture. Just like furniture in a home, the placement of DNA elements matters - and sometimes, a gene knows exactly how to keep the best seat in the room.