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Nat Commun. 2017 Nov 24;8(1):1753. doi: 10.1038/s41467-017-01962-x.

Single-cell absolute contact probability detection reveals chromosomes are organized by multiple low-frequency yet specific interactions.

Author information

1
Centre de Biochimie Structurale, CNRS UMR5048, INSERM U1054, Université de Montpellier, 29 rue de Navacelles, 34090, Montpellier, France.
2
CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 4, 08028, Barcelona, Spain.
3
Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation (CRG), Dr. Aiguader 88, 08003, Barcelona, Spain.
4
Universitat Pompeu Fabra (UPF), Barcelona, 08010, Spain.
5
ICREA, Pg. Lluís Companys 23, 08010, Barcelona, Spain.
6
Institut de Génétique Humaine, CNRS UMR 9002, Université de Montpellier, 141 rue de la Cardonille, 34396, Montpellier, France.
7
Epigenetics of Stem Cells, Department of Stem Cell and Developmental Biology, Institut Pasteur, CNRS UMR3738, 25 rue du Docteur Roux, 75015, Paris, France.
8
Department of Computer Science, National Chengchi University, 11605, Taipei City, Taiwan.
9
Institut de génétique et de biologie moléculaire et cellulaire, CNRS UMR 7104 - Inserm U 964, 67404, Illkirch, France.
10
Centre de Biochimie Structurale, CNRS UMR5048, INSERM U1054, Université de Montpellier, 29 rue de Navacelles, 34090, Montpellier, France. marcelo.nollmann@cbs.cnrs.fr.

Abstract

At the kilo- to megabase pair scales, eukaryotic genomes are partitioned into self-interacting modules or topologically associated domains (TADs) that associate to form nuclear compartments. Here, we combine high-content super-resolution microscopies with state-of-the-art DNA-labeling methods to reveal the variability in the multiscale organization of the Drosophila genome. We find that association frequencies within TADs and between TAD borders are below ~10%, independently of TAD size, epigenetic state, or cell type. Critically, despite this large heterogeneity, we are able to visualize nanometer-sized epigenetic domains at the single-cell level. In addition, absolute contact frequencies within and between TADs are to a large extent defined by genomic distance, higher-order chromosome architecture, and epigenetic identity. We propose that TADs and compartments are organized by multiple, small-frequency, yet specific interactions that are regulated by epigenetics and transcriptional state.

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