After a decade of research, the NIH 4D Nucleome program on July 23 delivered a wealth of new insights into how spatial changes in chromatin structure and DNA methylation regulate gene expression in health and disease. In a collection of eight papers published in Science and Science Advances, researchers describe how they have applied single-cell level multi-omics data and tools and techniques developed in the first part of the 4D Nucleome program to track changes in the noncoding part of the genome that are involved in heart disease, Alzheimer’s disease, brain aging, retinal health and immune cell development.