RT Journal Article
SR Electronic
T1 Formation of Chromosomal Domains in Interphase by Loop Extrusion
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 024620
DO 10.1101/024620
A1 Geoffrey Fudenberg
A1 Maxim Imakaev
A1 Carolyn Lu
A1 Anton Goloborodko
A1 Nezar Abdennur
A1 Leonid A. Mirny
YR 2016
UL http://biorxiv.org/content/early/2016/03/15/024620.abstract
AB Topologically Associating Domains (TADs) are fundamental structural and functional building blocks of human interphase chromosomes, yet mechanisms of TAD formation remain unknown. 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 can produce TADs as determined by our analyses of Hi-C data. Contrary to typical illustrations, each TAD consists of multiple dynamically formed loops, rather than a single static loop. Our model 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 depletion of CTCF versus cohesin. The emerging picture is that TADs arise from actively forming, growing, and dissociating loops, presenting a framework for understanding interphase chromosomal organization.