Chromosome organization by one-sided and two-sided loop extrusion

Banigan, Edward J.; Berg, A. van den; Brandão, Hugo B.; Marko, John F.; Mirny, Leonid A.

doi:10.7554/elife.53558

Cited by 107 publications

(130 citation statements)

References 172 publications

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“…Hi-C maps evocative of experimental data 41 , here we suggest that one-sided extrusion may frequently occur on fully chromatized DNA that dominates in vivo. While recent simulations highlight strong TAD corner peaks as a characteristic feature of two-sided loop extrusion, 41 such peaks are relatively rare in Hi-C data without extensive averaging (see Fig. 3 and Extended Data Figs.…”

Section: Single-molecule Experiments Show That Nucleosomes Impede Cohmentioning

confidence: 51%

Loops and the activity of loop extrusion factors constrain chromatin dynamics

Bailey

Surovtsev

Williams

et al. 2020

Preprint

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Chromosome conformation capture techniques (e.g Hi-C) reveal that intermediate-scale chromatin organization is comprised of “topologically associating domains” (TADs) on the tens to thousands of kb scale.1–5 The loop extrusion factor (LEF) model6–10 provides a framework for how TADs arise: cohesin or condensin extrude DNA loops, until they encounter boundary elements. Despite recent in vitro studies demonstrating that cohesin and condensin can drive loop formation on (largely) naked DNA11–13, evidence supporting the LEF model in living cells is lacking. Here, we combine experimental measurements of chromatin dynamics in vivo with simulations to further develop the LEF model. We show that the activity of the INO80 nucleosome remodeler enhances chromatin mobility, while cohesin and condensin restrain chromatin mobility. Motivated by these findings and the observations that cohesin is loaded preferentially at nucleosome-depleted transcriptional start sites14–18 and its efficient translocation requires nucleosome remodeling19–23 we propose a new LEF model in which LEF loading and loop extrusion direction depend on the underlying architecture of transcriptional units. Using solely genome annotation without imposing boundary elements, the model predicts TADs that reproduce experimental Hi-C data, including boundaries that are CTCF-poor. Furthermore, polymer simulations based on the model show that LEF-catalyzed loops reduce chromatin mobility, consistent with our experimental measurements. Overall, this work reveals new tenets for the origins of TADs in eukaryotes, driven by transcription-coupled nucleosome remodeling.

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Section: Single-molecule Experiments Show That Nucleosomes Impede Cohmentioning

confidence: 51%

Loops and the activity of loop extrusion factors constrain chromatin dynamics

Bailey

Surovtsev

Williams

et al. 2020

Preprint

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“…We use a fixed-time-step Monte Carlo algorithm as in previous work 11 . The 1D extrusion simulations proceed with time-steps equivalent to 1/20 th of a second.…”

Section: Methodsmentioning

confidence: 99%

“…We coupled each of the 1D loop-extrusion simulations to a model of a polymer chain 11 and performed molecular dynamics simulations using Polychrom 13 , a Python API that wraps the molecular dynamics simulation software OpenMM 14 . In this coupled model, LEFs act as a bond between the two monomers.…”

Section: Methodsmentioning

confidence: 99%

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DNA-loop extruding SMC complexes can traverse one anotherin vivo

Brandão

Ren

Karaboja

et al. 2020

Preprint

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The spatial organization of chromosomes by structural maintenance of chromosomes (SMC) complexes is vital to organisms from bacteria to humans. SMC complexes were recently found to be motors that extrude DNA loops. It remains unclear, however, what happens when multiple SMC complexes encounter one another in vivo on the same DNA, how encounters are resolved, or how interactions help organize an active genome. Here, we set up a crash-course track system to study what happens when SMC complexes encounter one another. Using the parS/ParB system, which loads SMC complexes in a targeted manner, we engineered the Bacillus subtilis chromosome to have multiple SMC loading sites. Chromosome conformation capture (Hi-C) analyses of over 20 engineered strains show an amazing variety of never-before-seen chromosome folding patterns. Polymer simulations indicate these patterns require SMC complexes to traverse past each other in vivo, contrary to the common assumption that SMC complexes mutually block each others extrusion activity. Our quantitative model of bypassing predicted that increasing the numbers of SMCs on the chromosome could overwhelm the bypassing mechanism, create SMC traffic jams, and lead to major chromosome reorganization. We validated these predictions experimentally. We posit that SMC complexes traversing one another is part of a larger phenomenon of bypassing large steric barriers which enables these loop extruders to spatially organize a functional and busy genome.

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“…There have been previous attempts to model this loop formation process through the action of SMC proteins. A common feature of these models is that the motion of these SMC proteins on the DNA backbone was assumed to be active, driven by the consumption of ATP [2–4, 18, 22], motivated by the presence of ATPase activity in the SMC proteins, and the fast timescales for the formation of these large loops. Such active SMC proteins have been theoretically shown to compact the chromosome effectively with stable loops formed by stacks of SMC proteins at the base of the loops [22].…”

Section: Introductionmentioning

confidence: 99%

The accidental ally: Nucleosomal barriers can accelerate cohesin mediated loop formation in chromatin

Maji¹,

Padinhateeri²,

Mitra³

2019

Preprint

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An important question in the context of the 3D organization of chromosomes is the mechanism of formation of large loops between distant base pairs. Recent experiments suggest that the formation of loops might be mediated by Loop Extrusion Factor proteins like cohesin. Experiments on cohesin have shown that cohesins walk diffusively on the DNA, and that nucleosomes act as obstacles to the diffusion, lowering the permeability and hence reducing the effective diffusion constant. An estimation of the times required to form the loops of typical sizes seen in Hi-C experiments using these low effective diffusion constants leads to times that are unphysically large. The puzzle then is the following, how does a cohesin molecule diffusing on the DNA backbone achieve speeds necessary to form the large loops seen in experiments? We propose a simple answer to this puzzle, and show that while at low densities, nucleosomes act as barriers to cohesin diffusion, beyond a certain concentration, they can reduce loop formation times due to a subtle interplay between the nucleosome size and the mean linker length. This effect is further enhanced on considering stochastic binding kinetics of nucleosomes on the DNA backbone, and leads to predictions of lower loop formation times than might be expected from a naive obstacle picture of nucleosomes. 2 structure inside the nucleus remains an important open question [16, 40, 41, 62]. An 3 ubiquitous structural motif, as observed through 14, 25, 47] and other 4 experiments [34, 36, 50] are the formation of large loops, ranging from kilobases to 5 megabases. These loops play both a structural as well as functional roles, bringing 6 together regions of the DNA that are widely spaced along the backbone [1, 9, 35]. In 7 recent years, much work has been done in trying to understand the mechanism of 8 formation of these large loops. There is now a significant body of experimental 9 observations that implicate a class of proteins called the Structural maintenance of 10 chromosome (SMC) protein complexes -such as cohesin and condensin in the formation 11 and maintenance of these large chromosomal loops [19, 20, 28, 33, 54, 55, 58, 59, 64]. 12 Structural maintenance of chromosome (SMC) protein complexes are known to play 13 a major role in chromosome segregation in interphase and mitosis . Both cohesin and 14 condensin consists of SMC subunits and share structural similarities. SMC subunits 15 1/15 (SMC1, SMC3 in cohesin and SMC2, SMC4 in condensin) fold back on themselves to 16 form approximately a 50nm long arm. These two arms are then connected at one end 17 by a hinge domain and other two ends which have ATPase activity are connected by a 18 kleisin subunit (RAD21 in cohesin and condensin-associated protein H2 [CAPH2] in 19condensin)to form a ring like structure of the whole complex [5, 21, 26, 27, 42, 43, 48]. 20This ring like structure has been hypothesized to form a topological association with the 21 DNA backbone [38, 46]. In particular, experiments on cohesin have shown that such 22 topol...

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Chromosome organization by one-sided and two-sided loop extrusion

Cited by 107 publications

References 172 publications

Loops and the activity of loop extrusion factors constrain chromatin dynamics

Loops and the activity of loop extrusion factors constrain chromatin dynamics

DNA-loop extruding SMC complexes can traverse one anotherin vivo

The accidental ally: Nucleosomal barriers can accelerate cohesin mediated loop formation in chromatin

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