The article explores the three-dimensional organization of genomes and the interpretation of chromatin interaction data. It discusses the development of molecular, genomic, and computational approaches based on chromosome conformation capture technology (3C, 4C, 5C, and Hi-C) to study the spatial organization of genomes at unprecedented resolution. The authors describe several statistical and computational methods for analyzing chromatin interaction datasets, including identifying frequent interactions, restraint-based modeling, and polymer physics approaches. These methods help uncover principles that determine the spatial organization of chromosomes, reveal novel layers of chromatin structure, and relate these structures to gene expression and regulation. The article also highlights the insights gained from imaging techniques and the importance of understanding the complex nature of comprehensive chromatin interaction datasets. Finally, it discusses the formation of topologically associating domains (TADs) and the use of polymer physics to interpret interaction data, emphasizing the role of topological constraints in chromosome folding.The article explores the three-dimensional organization of genomes and the interpretation of chromatin interaction data. It discusses the development of molecular, genomic, and computational approaches based on chromosome conformation capture technology (3C, 4C, 5C, and Hi-C) to study the spatial organization of genomes at unprecedented resolution. The authors describe several statistical and computational methods for analyzing chromatin interaction datasets, including identifying frequent interactions, restraint-based modeling, and polymer physics approaches. These methods help uncover principles that determine the spatial organization of chromosomes, reveal novel layers of chromatin structure, and relate these structures to gene expression and regulation. The article also highlights the insights gained from imaging techniques and the importance of understanding the complex nature of comprehensive chromatin interaction datasets. Finally, it discusses the formation of topologically associating domains (TADs) and the use of polymer physics to interpret interaction data, emphasizing the role of topological constraints in chromosome folding.