Scrambled DNA reveals new insights into how our genome works

What happens when you radically rearrange your furniture? You might discover that the couch really should have been near the window all along, while the cabinet suddenly feels awkwardly in the way in its new spot in the corner. Something similar applies to our DNA: the complete instruction manual of our bodies is folded neatly inside the cell nucleus, and every part seems to have its own fixed location. But why? And what happens when you shuffle everything around? In other words: scrambled DNA.

Researchers at the Netherlands Cancer Institute and Oncode Institute, have developed a method that lets them do exactly that. The technique enables them to cut, flip, and move pieces of DNA, sometimes across large distances, allowing them to radically but precisely rearrange the layout of our DNA, and see what happens.

This method is different from well-known tools like CRISPR. Whereas CRISPR usually makes small, targeted changes, this new approach can move large stretches of DNA in many different ways. For the first time, researchers can systematically explore how the position of DNA influences whether genes are active or silent.

The right environment

The team has now used this approach to carry out two major studies. In the first, published in Science, they relocated a gene thousands of times to nearby spots. The surprising result: the gene works best in its original location.

Genes are normally regulated by special pieces of DNA called enhancers that act like switches, controlling whether a gene is on or off and how active it is. Even placing the gene closer to one of these enhancers didn't necessarily make it work better. In fact, the gene even became less active at times, or shut down completely. "We thought genes would always work better when they're closer to the enhancer, but it seems like that's not the case. The environment matters just as much," says PhD student Mathias Eder.

Anchored at the edge

In the second study, published in the scientific journal Nature Structural & Molecular Biology, the researchers focused on large stretches of DNA that always sit at the edge of the cell nucleus, also called LADs. Using their "scrambling" technique, they broke these regions into pieces, flipped them around, or moved them to new locations. What they found: LADs aren't held in place by a single glue point, but by a whole series of knots. Some knots hold tight, while others come apart more easily.

These findings show that the arrangement of DNA elements isn't random, but part of a sophisticated system of positions and connections. Understanding how this system works helps researchers figure out how genes are switched on and off, and why these processes sometimes go wrong in diseases like cancer.

The new scrambled-DNA method is a powerful tool for this research and for many other questions about the architecture of our DNA. As postdoctoral researcher Lise Dauban puts it: "We've only just caught a glimpse of the rules. Now that we can rearrange DNA itself, we can finally start to uncover them."

Research at the Netherlands Cancer Institute is financially supported by KWF Dutch Cancer Society and the AVL Foundation.

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