Two independent modes of chromatin organization are revealed by cohesin removal

Wibke Schwarzer*, Nezar Abdennur*, Anton Goloborodko*, Aleksandra Pekowska, Geoffrey Fudenberg, Yann Loe-Mie, Nuno A Fonseca, Wolfgang Huber, Christian H. Haering, Leonid Mirny & Francois Spitz.

Nature 551, 51–56. doi:10.1038/nature24281

bioRxiv (Dec, 2016) doi:10.1101/094185


Imaging and chromosome conformation capture studies have revealed several layers of chromosome organization, including segregation into megabase-large active and inactive compartments, and partitioning into sub-megabase domains (TADs). Yet, it remains unclear how these layers of organization form, interact with one another and impact genome functions. Here, we show that deletion of the cohesin-loading factor Nipbl, in mouse liver, leads to a dramatic reorganization of chromosomal folding. TADs and associated peaks vanish globally, even in the absence of transcriptional changes. In contrast, compartmental segregation is preserved and even reinforced. Strikingly, the disappearance of TADs unmasks a finer compartment structure that accurately reflects the underlying epigenetic landscape. These observations demonstrate that the 3D organization of the genome results from the interplay of two independent mechanisms: 1) cohesin-independent segregation of the genome into fine-scale compartments, defined by chromatin state; 2) cohesin-dependent formation of TADs, possibly by loop extrusion, which contributes to guide distant enhancers to their target genes.

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In ΔNipbl liver cells, TADs (local enrichment patterns: squares, lines, peaks) vanish completely, while compartmentalization (the checkerboard pattern) is preserved. Based on ED Fig 7a.
In gene dense regions, compartmentalization in ΔNipbl becomes not only stronger but finer. Based on Fig 3a.
WT vs TAM vs ΔNipbl conditions, locked by zoom and location, with overlaid eigenvector tracks above.
WT vs ΔNipbl context views (top) with zoomed-in detail views (bottom) connected by view projections (grey squares).