Our DNA is often pictured as a simple spiral, like a piece of rope held taut. But inside cells, it folds into a complex three-dimensional structure, with 2 meters (6.6 feet) of DNA scrunched like a headphone wire in a pocket. This bundled architecture plays a crucial role in how genes are switched on and off. Understanding these interactions is key to interpreting genetic studies of disease and can help develop targeted treatments.

Genes—the instructions for making proteins—are regulated by two types of DNA regions, called promoters and enhancers. Promoters are located at the start of each gene and directly load the machinery that reads it to produce RNA, a template for making proteins. In contrast, enhancers, which act like “molecular switches” boosting gene activity in the right cell and condition, may be found much further from the genes they control: sometimes many thousands or even millions of DNA letters away. When DNA folds in the 3D space of the cell’s nucleus, these enhancers loop around to physically contact the genes they regulate.

Understanding how enhancers work and which genes they control is particularly important because genome-wide association studies—large-scale efforts comparing the DNA of thousands of people to identify small genetic differences linked to disease—have revealed many genetic variants associated with complex conditions such as Crohn’s disease that sit within these regions. Crohn’s disease is a common form of inflammatory bowel disease, which affects around 1 in 100 people globally and currently has no known cure.