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Chromosome structure and genome organization in early mammalian development

Final Report Summary - DEVOCHROMO (Chromosome structure and genome organization in early mammalian development)

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. We used 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 highlights the importance of cell cycle phase in interpretation of chromosome conformation maps. The maternal and paternal genomes, each with very different developmental histories and epigenetic profiles meet for the first time after fertilization, and cooperate to accomplish one of the greatest enigmas in biology, the creation of a multi-cellular organism with hundreds of different cell-types, each with distinct gene expression programs. Recent developments point to the 3D organization of the genome and chromosome folding as key determinants in regulation of genome functions and gene expression. Here we present allele-specific, single-cell Hi-C data for hundreds of F1 hybrid mouse embryo cells spanning pre-implantation development, from the oocyte to the 64-cell stage. The results reveal remarkable chromosome choreography in the meeting of the two genomes.