3D genome organization atlas

After 10 years, members of the 4D Nucleome consortium have successfully completed the first phase of a project that aims to map the 3D organization of the human genome and how it changes over time, the fourth dimension (Nature 2025, DOI:0.1038/s41586-025-09890-3).By taking 3D snapshots of how DNA is folded inside the nucleus of two different human cell types—embryonic stem cells and fibroblasts—the researchers were able to measure how DNA is packaged, looped, and positioned within the nucleus. These organizational structures go beyond just packaging the genome into a small space; they also physically bring distant regulatory switches—like enhancers—into direct contact with the genes they control.The genome folds in a nonrandom way at multiple levels. For example, DNA wraps around histone proteins to form chromatin, which can be biochemically modified to control how tightly DNA is wound and how easily genes can be accessed for expression. It is only during cell division that we see DNA wound so tightly into chromosomes that take the iconic X-shaped structure.One way that DNA structure can regulate gene expression is with topologically associating domains (TADs), which are loops of DNA that form when a ring-shaped protein called cohesin lands on the DNA strands and pushes the loop out through its center. Through looping, the promoter of a gene within a TAD can be brought into proximity with its enhancers to activate transcription.Job Dekker at the University of Massachusetts Chan Medical School and colleagues used a variety of methods to determine the detailed folding of genomes