A new 3D structure of the cancer-linked protein BRD4, bound to its cellular partner, has revealed how this protein interacts with chromosomes, potentially offering new insights for future disease treatments. BRD4 plays a vital role in processes such as reading, copying, and repairing DNA, and it helps determine how different types of cells are formed. It has been linked to various cancers and is a promising target for developing new therapies. The study, led by scientists at Penn State and published in Molecular Cell, found that BRD4 can attach to DNA-packaging structures in cells even without a molecular signal that was previously thought to be essential for this interaction. BRD4 belongs to a family of proteins that contain structures called bromodomains. These domains allow BRD4 to bind to chromosomes, where it helps regulate when other genes are activated or silenced. It was previously believed that BRD4 binds to the nucleosome—the repeating structure of DNA and proteins in chromosomes—only when its bromodomains interact with proteins called histones that have a specific chemical tag attached. Using a technique called cryo-electron microscopy (cryo-EM), which can capture images at near-atomic resolution, the researchers found that BRD4 binds to the modified histone as expected, but it also binds directly to the DNA within the nucleosome. The structure also showed that when one of BRD4's bromodomains binds to a modified histone, it creates a platform for other proteins to interact with BRD4. In further experiments, the team tested whether BRD4 could still bind to nucleosomes without the chemical tags on the histones. Surprisingly, they found that BRD4 binds to unmodified histones with nearly the same strength as it does to modified ones. This finding challenges previous assumptions, as it was believed that the acetylation tag on histones was necessary for BRD4 to bind. The study suggests that certain regions of the BRD4 protein allow it to bind to unmodified histones. While it is not yet known if this occurs in living cells, the discovery could lead to a better understanding of how BRD4 and similar proteins function in various biological contexts.