Cell Reports
Volume 15, Issue 9, 31 May 2016, Pages 2038-2049
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Article
Formation of Chromosomal Domains by Loop Extrusion

https://doi.org/10.1016/j.celrep.2016.04.085Get rights and content
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Highlights

  • TADs can be formed by loop extrusion limited by boundary elements

  • Polymer simulations and genomic analyses were jointly used to test this proposal

  • Proposed roles of cohesin and CTCF reconcile diverse experimental observations

Summary

Topologically associating domains (TADs) are fundamental structural and functional building blocks of human interphase chromosomes, yet the mechanisms of TAD formation remain unclear. Here, we propose that loop extrusion underlies TAD formation. In this process, cis-acting loop-extruding factors, likely cohesins, form progressively larger loops but stall at TAD boundaries due to interactions with boundary proteins, including CTCF. Using polymer simulations, we show that this model produces TADs and finer-scale features of Hi-C data. Each TAD emerges from multiple loops dynamically formed through extrusion, contrary to typical illustrations of single static loops. Loop extrusion both explains diverse experimental observations—including the preferential orientation of CTCF motifs, enrichments of architectural proteins at TAD boundaries, and boundary deletion experiments—and makes specific predictions for the depletion of CTCF versus cohesin. Finally, loop extrusion has potentially far-ranging consequences for processes such as enhancer-promoter interactions, orientation-specific chromosomal looping, and compaction of mitotic chromosomes.

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6

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