Principles of genome folding into topologically associating domains

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Science Advances  10 Apr 2019:
Vol. 5, no. 4, eaaw1668
DOI: 10.1126/sciadv.aaw1668


  • Fig. 1 Hierarchical folding of the eukaryotic genome.

    (A) Schematic view of chromosome folding inside the nucleus. The finest layer of chromatin folding is at the DNA-histone association level, forming nucleosomes organized into the ~11-nm chromatin fiber (133). Chromatin is packed at different nucleosome densities depending on gene regulation and folds at the submegabase scale into higher-order domains of preferential internal interactions, referred to as TADs. At the chromosomal scale, chromatin is segregated into active “A” and repressed “B” compartments of interactions, reflecting preferential contacts between chromatin regions of the same epigenetic features. Individual chromosomes occupy their own space within the nucleus, forming chromosome territories. (B) Schematic representation of Hi-C maps at different genomic scales, reflecting the different layers of higher-order chromosome folding. Genomic coordinates are indicated on both axes, and the contact frequency between regions is represented by a color code. At the submegabase scale, TADs appear as squares along the diagonal enriched in interactions, separated by contact depletion zones delimited by TAD boundaries. At the chromosomal scale, chromatin long-range interactions form a characteristic plaid pattern of two mutually excluded A and B compartments. Last, intrachromosomal interactions are overrepresented compared to interchromosomal contacts, consistent with the formation of individual chromosome territories.

  • Fig. 2 Examples of Hi-C profiles from different species.

    Hi-C maps [visualized with Juicebox (134)] of different species (24, 67, 75, 90, 135) showing more or less pronounced 3D partitioning of the genome. TADs are not obvious in Arabidopsis genome, but boundary-like regions and insulated genome units are discernible. In Drosophila, TADs are well demarcated and correlate well with the epigenetic landscape. A specific feature of mammalian TADs is the presence of “corner peaks,” i.e., peaks of interactions at the edges of TADs (indicated by black circles), revealing the presence of chromatin loops.

  • Fig. 3 Schematic representation of chromatin folding in Drosophila and mammals.

    (A) In Drosophila, both TADs and compartments correspond to epigenetic domains that preferentially fold within themselves and in far-cis with homotypic TADs (1). Large repressed chromatin region forms prominent and condensed TADs (2), separated by transcribed genes that can form clusters of small active TAD or inter-TAD–like regions of decondensed chromatin (3). (B) In mammals, the “loop extrusion model” proposed for TAD formation involves a loop extrusion factor, here cohesin, loaded on the chromatin by Nipbl and unloaded by Wapl. Cohesin extrudes chromatin until it dissociates, bumps into another cohesin, or reaches the border of the TAD bound by CTCF proteins in inverted orientation or by other boundary components. These loops are seen as a strong peak of interaction between TAD borders (1). Insulation can also be observed at active transcription start sites (2), and as recently suggested, the loop extrusion process could compete with the local segregation of active and inactive chromatin by mixing them (3) (45).

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