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Formation of Chromosomal Domains by Loop Extrusion
#MMPMID27210764
Fudenberg G
; Imakaev M
; Lu C
; Goloborodko A
; Abdennur N
; Mirny LA
Cell Rep
2016[May]; 15
(9
): 2038-49
PMID27210764
show ga
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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