Formation of Chromosomal Domains in Interphase by Loop Extrusion

Abstract

SUMMARYTopologically 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.

The 3D Genome as Moderator of Chromosomal Communication

“…Recent simulation studies have shown that although formation of a 30Kb chromatin loop can facilitate intra-loop interactions, insulation of the loop interior from the exterior is very modest with about 30% reduction in the contact frequency Benedetti et al, 2014; Doyle et al, 2014). Polymer simulations (Fudenberg et al, 2015) have also shown that even a bulky protein assembly on a chromatin fiber cannot serve as a reliable insulator providing no insulation beyond the size of the bulky assembly. Similarly, local changes in the flexibility of the chromatin fiber that can be induced by an insulator cannot provide robust insulation between regions distant from the insulator along the genome (Fudenberg et al, 2015).…”

The second decade of 3C technologies: detailed insights into nuclear organization

“…The extrusion model is favored. It proposes that DNA is actively extruded through cohesin rings until reaching two compatible roadblocks that stabilize the thereby formed chromatin loop (Fudenberg et al 2015;Sanborn et al 2015). For roadblocks to be compatible, it is assumed that CTCF molecules must be bound in a convergent orientation.…”

CTCF: making the right connections

“…3). This is an attractive model because its geometry gives rise to exactly the kind of (largely) nonoverlapping pattern of loop domains observed in vivo as well as the intraloop folding patterns deduced from the Hi-C data (Rao et al 2014;Fudenberg et al 2015;Sanborn et al 2015;Dekker and Mirny 2016). Theory and experiment do not necessarily agree in detail, possibly a reflection of the ways in which evolution has elaborated on simple polymer physics.…”