Cell-cycle dynamics of chromosomal organization at single-cell resolution

• Published in: Nature (London) Vol. 547; no. 7661; pp. 61 - 67
• Main Authors: Nagano, Takashi, Lubling, Yaniv, Várnai, Csilla, Dudley, Carmel, Leung, Wing, Baran, Yael, Mendelson Cohen, Netta, Wingett, Steven, Fraser, Peter, Tanay, Amos
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.07.2017; Nature Publishing Group
• Subjects: 631/337/103; 631/337/386; Animals; Architecture; Cell Compartmentation; Cell cycle; Cell Cycle - genetics; Cell Cycle - physiology; Chromosomes; Chromosomes, Mammalian - chemistry; Chromosomes, Mammalian - genetics; Chromosomes, Mammalian - metabolism; Conformation; Cytological research; Deoxyribonucleic acid; Dimensional stability; DNA; DNA biosynthesis; Epigenesis, Genetic; G2 phase; Gene mapping; Gene silencing; Genetic aspects; Genomes; Haploidy; Humanities and Social Sciences; Imaging, Three-Dimensional; Insulation; Interphase; Mice; Mouse Embryonic Stem Cells - cytology; multidisciplinary; Replication; Reproducibility of Results; Science; Single-Cell Analysis - methods; Structural models; Three dimensional models; Topology
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature23001

Chromosomes in proliferating metazoan cells undergo marked structural metamorphoses every cell cycle, alternating between highly condensed mitotic structures that facilitate chromosome segregation, and decondensed interphase structures that accommodate transcription, gene silencing and DNA replication. Here we use single-cell Hi-C (high-resolution chromosome conformation capture) analysis to study chromosome conformations in thousands of individual cells, and discover a continuum of cis -interaction profiles that finely position individual cells along the cell cycle. We show that chromosomal compartments, topological-associated domains (TADs), contact insulation and long-range loops, all defined by bulk Hi-C maps, are governed by distinct cell-cycle dynamics. In particular, DNA replication correlates with a build-up of compartments and a reduction in TAD insulation, while loops are generally stable from G1 to S and G2 phase. Whole-genome three-dimensional structural models reveal a radial architecture of chromosomal compartments with distinct epigenomic signatures. Our single-cell data therefore allow re-interpretation of chromosome conformation maps through the prism of the cell cycle. Single-cell Hi-C analysis in thousands of mouse embryonic stem cells shows that chromosomal compartments, topological-associated domains and long-range loops all have distinct cell-cycle dynamics. Chromosomal organization dynamics Eukaryotic chromosomes undergo a cycle of compaction and decondensation during the cell cycle. Here, Peter Fraser and colleagues have developed an improved single-cell Hi-C method to characterize the 3D organization of chromosomes through the cell cycle in thousands of individual mouse embryonic stem cells. They find that chromosomal compartments, topological-associated domains and loops are each governed by distinct dynamics and reveal a continuum of dynamic chromosomal structural features throughout the cell cycle. The results will be a new point of reference for interpreting chromosome conformation Hi-C maps.