Regulation of single-cell genome organization into TADs and chromatin nanodomains

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Szabo, Quentin | Donjon, Axelle | Jerković, Ivana | Papadopoulos, Giorgio | Cheutin, Thierry | Bonev, Boyan | Nora, Elphège | Bruneau, Benoit | Bantignies, Frederic | Cavalli, Giacomo

Edité par CCSD ; Nature Publishing Group -

International audience. 20 The genome folds into a hierarchy of three-dimensional (3D) structures within the nucleus. At 21 the sub-megabase scale, chromosomes form topologically associating domains (TADs) 1-4. 22 However, how TADs fold in single-cells remains elusive. Here, we revealed TAD features 23 inaccessible to cell-population analysis by using super-resolution microscopy. TAD structures 24 and physical insulation associated with their borders are variable between individual cells, yet 25 chromatin intermingling is enriched within TADs compared to adjacent TADs in most cells. The 26 spatial segregation of TADs is further exacerbated during cell differentiation. Favored 27 interactions within TADs are regulated by cohesin and CTCF through distinct mechanisms: 28 cohesin generates chromatin contacts and intermingling while CTCF prevents inter-TAD 29 contacts. Furthermore, TADs are subdivided into discrete nanodomains which persist in cells 30 depleted of CTCF or cohesin, whereas disruption of nucleosome contacts alters their structural 31 2 organization. Altogether, these results provide a physical basis for the folding of individual 32 chromosomes at the nanoscale. 33 34

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