The study introduces single-cell Hi-C, a method to determine chromosomal contacts in individual nuclei, and combines it with genome-wide statistical analysis and structural modeling of single-copy X chromosomes. The researchers found that individual chromosomes maintain domain organization at the megabase scale but show variable cell-to-cell chromosome territory structures at larger scales. Despite this variability, active gene domains tend to localize to the boundaries of territories, a hallmark of chromosomal conformation. Single-cell Hi-C data bridges the gap between genomics and microscopy studies, demonstrating how modular organization underlies dynamic chromosome structure and how this structure is probabilistically linked with genome activity patterns. The study also reveals that inter-domain and trans-chromosomal contact structures are highly variable between individual cells, while intra-domain structure is conserved. Additionally, active domains maintain their intra-domain organization while only partially losing intra-chromosomal contacts with other domains, suggesting that chromosomal territories are robustly maintained despite trans-chromosomal contacts.The study introduces single-cell Hi-C, a method to determine chromosomal contacts in individual nuclei, and combines it with genome-wide statistical analysis and structural modeling of single-copy X chromosomes. The researchers found that individual chromosomes maintain domain organization at the megabase scale but show variable cell-to-cell chromosome territory structures at larger scales. Despite this variability, active gene domains tend to localize to the boundaries of territories, a hallmark of chromosomal conformation. Single-cell Hi-C data bridges the gap between genomics and microscopy studies, demonstrating how modular organization underlies dynamic chromosome structure and how this structure is probabilistically linked with genome activity patterns. The study also reveals that inter-domain and trans-chromosomal contact structures are highly variable between individual cells, while intra-domain structure is conserved. Additionally, active domains maintain their intra-domain organization while only partially losing intra-chromosomal contacts with other domains, suggesting that chromosomal territories are robustly maintained despite trans-chromosomal contacts.