Large-scale chromosome structure and spatial nuclear arrangement have been linked to control of gene expression and DNA replication and repair. Genomic techniques based on chromosome conformation capture (3C) assess contacts for millions of loci simultaneously, but do so by averaging chromosome conformations from millions of nuclei. Here we introduce single-cell Hi-C, combined with genome-wide statistical analysis and structural modelling of single-copy X chromosomes, to show that individual chromosomes maintain domain organization at the megabase scale, but show variable cell-to-cell chromosome structures at larger scales. Despite this structural stochasticity, localization of active gene domains to boundaries of chromosome territories is a hallmark of chromosomal conformation. Single-cell Hi-C data bridge current gaps between genomics and microscopy studies of chromosomes, demonstrating how modular organization underlies dynamic chromosome structure, and how this structure is probabilistically linked with genome activity patterns. A novel genomic technique, single-cell Hi-C, detects thousands of simultaneous chromatin contacts in a single cell; this is used to show that individual chromosomes maintain domain organization at the megabase scale, but that chromosome structures vary from cell to cell at larger scales. The latest genomic techniques such as Hi-C, based on chromosome conformation capture (3C), can detect chromatin interactions and provide a three-dimensional picture of chromosome organization in the nucleus. The resulting data, averaged over millions of gene loci, are not directly relevant to the organization of a single cell. Peter Fraser and colleagues have bridged the gap between genomics and microscopy studies by developing a single-cell Hi-C approach that allows the detection of thousands of simultaneous genomic contacts in an individual cell. Using the system together with a three-dimensional structural model of the X chromosome, the authors demonstrate how chromosome territory structures vary from cell to cell, particularly the interdomain and trans-chromosomal contacts.

Single-cell Hi-C reveals cell-to-cell variability in chromosome structure