Formation of Chromosomal Domains by Loop Extrusion

TLDR

Topologically associating domains (TADs) are key structural and functional units of human interphase chromosomes, yet their formation mechanisms remain unclear. The study proposes that loop extrusion drives TAD formation. Cis‑acting loop‑extruding factors, likely cohesins, progressively form larger loops that stall at TAD boundaries through interactions with boundary proteins such as CTCF. Polymer simulations show that loop extrusion generates TADs and Hi‑C–like features, with each TAD arising from multiple dynamic loops, thereby explaining CTCF motif orientation, protein enrichment at boundaries, and boundary deletion results, predicting differential CTCF versus cohesin depletion, and suggesting broad effects on enhancer‑promoter interactions, orientation‑specific looping, and mitotic chromosome compaction.

Abstract

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.