Loop stacking organizes genome folding from TADs to chromosomes.

Antonina Hafner, Minhee Park, Scott E Berger, Sedona E Murphy, Elphège P Nora, Alistair N Boettiger

Molecular cell 2023 May 04

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Although population-level analyses revealed significant roles for CTCF and cohesin in mammalian genome organization, their contributions at the single-cell level remain incompletely understood. Here, we used a super-resolution microscopy approach to measure the effects of removal of CTCF or cohesin in mouse embryonic stem cells. Single-chromosome traces revealed cohesin-dependent loops, frequently stacked at their loop anchors forming multi-way contacts (hubs), bridging across TAD boundaries. Despite these bridging interactions, chromatin in intervening TADs was not intermixed, remaining separated in distinct loops around the hub. At the multi-TAD scale, steric effects from loop stacking insulated local chromatin from ultra-long range (>4 Mb) contacts. Upon cohesin removal, the chromosomes were more disordered and increased cell-cell variability in gene expression. Our data revise the TAD-centric understanding of CTCF and cohesin and provide a multi-scale, structural picture of how they organize the genome on the single-cell level through distinct contributions to loop stacking. Copyright © 2023 Elsevier Inc. All rights reserved.

Citation

Antonina Hafner, Minhee Park, Scott E Berger, Sedona E Murphy, Elphège P Nora, Alistair N Boettiger. Loop stacking organizes genome folding from TADs to chromosomes. Molecular cell. 2023 May 04;83(9):1377-1392.e6