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.