Researchers have produced the most detailed maps yet of how human DNA folds and reorganizes in three dimensions and over time. This work, led by scientists at Northwestern University as part of the 4D Nucleome Project, highlights how genome architecture influences gene activity and disease risk. The findings, published in Nature, could accelerate the discovery of genetic mutations linked to illnesses like cancer.
In a significant advance for genetics, scientists at Northwestern University, collaborating on the 4D Nucleome Project, have created comprehensive maps of the human genome's three-dimensional organization and its changes over time. The research utilized human embryonic stem cells and fibroblasts to capture how DNA interacts, folds, and shifts during cell growth, function, and division. Published in the journal Nature in 2025, the study provides fresh insights into the physical arrangements that control gene expression.
DNA does not remain as a linear strand inside cells; it forms loops and compartments within the nucleus, which determine which genes activate or deactivate. This affects development, cell identity, and susceptibility to diseases. The team integrated multiple genomic techniques to generate a detailed dataset, revealing more than 140,000 chromatin loops per cell type, along with anchoring elements that regulate genes. They also classified chromosomal domains and produced high-resolution 3D models at the single-cell level, showing variations in structure tied to processes like transcription and DNA replication.
Co-corresponding author Feng Yue, the Duane and Susan Burnham Professor of Molecular Medicine at Northwestern's department of biochemistry and molecular genetics, emphasized the importance of this work. "Understanding how the genome folds and reorganizes in three dimensions is essential to understanding how cells function," Yue said. "These maps give us an unprecedented view of how genome structure helps regulate gene activity in space and time."
The researchers benchmarked various technologies to assess their effectiveness in detecting loops, domain boundaries, and positional changes. They further developed computational tools to predict genome folding from DNA sequences alone, enabling estimates of how genetic variants might alter 3D structures without lab experiments.
These advances hold promise for medicine, particularly since many disease-linked variants occur in non-coding regions. "The 3D genome organization provides a powerful framework for predicting which genes are likely to be affected by these pathogenic variants," Yue noted. Future applications may include targeting structural errors in cancers like leukemia through drugs such as epigenetic inhibitors, potentially leading to new diagnostics and therapies.
