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2015 ; 112
(47
): E6456-65
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Chromatin extrusion explains key features of loop and domain formation in
wild-type and engineered genomes
#MMPMID26499245
Sanborn AL
; Rao SS
; Huang SC
; Durand NC
; Huntley MH
; Jewett AI
; Bochkov ID
; Chinnappan D
; Cutkosky A
; Li J
; Geeting KP
; Gnirke A
; Melnikov A
; McKenna D
; Stamenova EK
; Lander ES
; Aiden EL
Proc Natl Acad Sci U S A
2015[Nov]; 112
(47
): E6456-65
PMID26499245
show ga
We recently used in situ Hi-C to create kilobase-resolution 3D maps of mammalian
genomes. Here, we combine these maps with new Hi-C, microscopy, and
genome-editing experiments to study the physical structure of chromatin fibers,
domains, and loops. We find that the observed contact domains are inconsistent
with the equilibrium state for an ordinary condensed polymer. Combining Hi-C data
and novel mathematical theorems, we show that contact domains are also not
consistent with a fractal globule. Instead, we use physical simulations to study
two models of genome folding. In one, intermonomer attraction during polymer
condensation leads to formation of an anisotropic "tension globule." In the
other, CCCTC-binding factor (CTCF) and cohesin act together to extrude unknotted
loops during interphase. Both models are consistent with the observed contact
domains and with the observation that contact domains tend to form inside loops.
However, the extrusion model explains a far wider array of observations, such as
why loops tend not to overlap and why the CTCF-binding motifs at pairs of loop
anchors lie in the convergent orientation. Finally, we perform 13 genome-editing
experiments examining the effect of altering CTCF-binding sites on chromatin
folding. The convergent rule correctly predicts the affected loops in every case.
Moreover, the extrusion model accurately predicts in silico the 3D maps resulting
from each experiment using only the location of CTCF-binding sites in the WT.
Thus, we show that it is possible to disrupt, restore, and move loops and domains
using targeted mutations as small as a single base pair.