Chromosome organization by one-sided and two-sided loop extrusion
- Institute for Medical Engineering & Science, Massachusetts Institute of Technology, United States
- Department of Physics, Massachusetts Institute of Technology, United States
- Harvard Graduate Program in Biophysics, Harvard University, United States
- Departments of Molecular Biosciences and Physics & Astronomy, Northwestern University, United States
Figures
Figure 1
Two-sided loop extrusion and variants of one-sided loop extrusion.
(a) A schematic of the loop extrusion model. The two subunits of the LEF bind to sites on a one-dimensional lattice representing DNA/chromatin. Over time, the subunits may translocate along DNA, and …
Figure 2 with 7 supplements
Chromosome compaction and structure in the one-sided loop extrusion model and model variants.
(a) Simulation snapshots of chromosomes compacted (left) and spatially resolved (right) by two-sided extrusion. (b) Simulation snapshots showing deficient compaction (left) and resolution (right) of …
Figure 2—figure supplement 1
Compaction in model with a mix of one- and two-sided LEFs.
(a) Strong linear compaction can only be achieved with a high fraction of two-sided LEFs. Colored dashed lines show prediction from mean-field theory (Banigan and Mirny, 2019) for compaction in the …
Figure 2—figure supplement 2
Measures of compaction and segregation with different densities of LEFs.
(a) Volumetric compaction of individual chromosomes and (b) scaled distance between the backbones of sister chromatids are shown for one-sided and two-sided extrusion (filled circles and open …
Figure 2—figure supplement 3
Loop sizes and LEF nesting explain the ineffectiveness of the semi-diffusive model.
(a) Example trajectory of a semi-diffusive LEF (blue) that is ratcheted open by another LEF (red) that binds within the extruded loop. (b) Mean loop sizes, ℓ, are small in the semi-diffusive model …
Figure 2—figure supplement 4
Models in which the active subunits of nested LEFs can push passive LEF subunits.
(a) Cartoon arch diagrams of ‘weak’ and ‘strong’ pushing models (top two and bottom two panels, respectively). One-sided LEFs are composed of active subunits (yellow) connected to passive subunits …
Figure 2—figure supplement 5
Defective compaction and segregation with 3D attractive interactions.
(a) Volumetric compaction plotted as a function of average attraction energy per monomer, for simulations with LEF-LEF attractive interactions (red) and attractive interactions between all monomers …
Figure 2—figure supplement 6
Fold linear compaction in pure one-sided extrusion models in which LEF residence times are altered by contact with other LEFs.
(a) Fold linear compaction in a model in which blocked one-sided LEFs have a different unbinding rate, kunbind,blocked. A LEF is blocked if it cannot extrude because it has encountered another LEF. …
Figure 2—figure supplement 7
Compaction and resolution of chromosomes with limited loop coverage.
(a) Arch diagram for a 1 Mb yeast chromosome with one-sided loop extruders with 40% loop coverage. (b) 3D polymer simulation image of the same chromosome. (c) Spatial resolution of 1 Mb chromatids …
Figure 3 with 8 supplements
TADs and corner peaks for variations on one-sided loop extrusion.
(a) A TAD in Hi-C of cortical neurons (Bonev et al., 2017), visualized by HiGlass (Kerpedjiev et al., 2018) at a resolution of 8 kb. Two characteristic features of TADs, stripes and dots, are …
Figure 3—figure supplement 1
Comparison of the contact probability as a function of genomic separation (scalings) of experiments (Haarhuis et al., 2017) and simulations to validate the chosen parameters for the simulations.
We present simulations for two-sided extrusion (left) and one-sided extrusion (right) for both wild-type (WT) and Wapl depletion conditions. With one monomer = 2 kb, λ = d = 200 kb for WT …
Figure 3—figure supplement 2
The primary and extended dot strength for two-sided, one-sided, semi-diffusive and switching LEFs.
(a) The definition of dot strength and primary and extended dots. The divergent color scale of the contact map emphasizes that dot strengths are computed on contact maps after computing …
Figure 3—figure supplement 3
Illustrations of loop extrusion by one-sided and two-sided LEFs.
(a) One-sided LEFs leave a gap between the passive LEF subunit and a barrier, unless they are loaded at a barrier (top row). Two-sided LEFs, on the other hand, can pair barriers while loading …
Figure 3—figure supplement 4
Sweep of the separation between LEFs and the processivity of LEFs for one-sided LEFs.
The TAD sizes from left to right are 200 kb, 400 kb, and 800 kb respectively. A processivity of λ = 200 kb gives scalings that best match wild-type conditions, while a processivity of λ = 2 Mb …
Figure 3—figure supplement 5
Sweep of the separation and the processivity of LEFs for two-sided LEFs.
The TAD sizes from left to right are 200 kb, 400 kb, and 800 kb respectively.
Figure 3—figure supplement 6
Sweep of the separation and the processivity of LEFs for one-sided LEFs with a loading bias at CTCF sites.
(a) Sweep of the separation between LEFs, d, for one-sided LEFs that load 1000 times more likely at a CTCF site as compared to an arbitrary site within the TAD, where each CTCF site has two loading …
Figure 3—figure supplement 7
Sweep of the separation and the processivity of LEFs for one-sided LEFs that may traverse each other.
The TADs are 200 kb and 400 kb in size.
Figure 3—figure supplement 8
Illustration of how the moving barrier mechanism (Brandão et al., 2019) combined with one-sided LEFs may result in dots in Hi-C of S. cerevisiae.
In the moving barrier model, RNA polymerase (RNAP) can push LEF subunits along chromatin. Left panel: ChIP-seq of the cohesin subunit Scc1 (Hu et al., 2015) and Hi-C (Ohno et al., 2019) in the S …
Figure 4 with 8 supplements
Effect of different extrusion rules on bacterial contact maps.
(a) Experimental Hi-C map for B. subtilis with a single parS site (SMC complex loading site) near the ori in the strain BDR2996 from Wang et al. (2015). Simulations of (b) the pure two-sided model …
Figure 4—figure supplement 1
Contact maps from simulations for different mixes of one- and two-sided LEFs and numbers of LEFs for bacterial chromosomes.
The fraction of one-sided LEFs increases from left to right, with 0% indicating the case of pure two-sided extrusion. The number of LEFs increases from top to bottom. Note that in these simulations, …
Figure 4—figure supplement 2
Contact maps from simulations for different values of the LEF stepping probability (per simulation step), with N = 5 LEFs on each chromosome.
These results indicate that the scaled diffusion rate, vdiff/v is the invariant quantity giving the contact maps their shape in the case of the model of a semi-diffusive LEF.
Figure 4—figure supplement 3
Sweep of the diffusive stepping rate and the number of LEFs for bacterial chromosomes.
Scaled diffusive stepping rate increases from left to right, and number of LEFs (i.e. extruding SMC complexes) increases from top to bottom.
Figure 4—figure supplement 4
Contact maps from 3D polymer simulations of an extrusion model in which LEFs may traverse each other and may occupy the same lattice sites.
Polymer simulations were performed as described in Appendix 3. Maps result form 10,000 different conformations of the bacterial chromosome polymer, with contacts captured with a radius of 6 monomer …
Figure 4—figure supplement 5
Contact maps from simulations for scaled switching rates and numbers of LEFs for bacterial chromosomes.
Switching probability per active translocation step increases from left to right and number of LEFs increases from top to bottom. Note that switching probabilities are given in simulation step units;…
Figure 4—figure supplement 6
Contact maps generated from molecular dynamics simulations as compared to the semi-analytical method.
Figure 4—figure supplement 7
Contact probability as a function of genomic distance generated from molecular dynamics simulations as compared to the semi-analytical method.
Data from molecular dynamics (MD) simulations is shown in orange, while the contact probability calculated from the semi-analytical method is shown in blue.
Figure 4—figure supplement 8
Generating Gaussian chain contact maps analytically from loop configurations.
The contact probability Pc(s) is calculated by converting the true genomic distance, s, to its effective genomic distance seff. For example, in (i), the effective genomic distance is simply harmonic …
Tables
Table 1
Summary of model results.
Each entry indicates whether there are parameters for the specified model (column headings) that can explain chromosome organization in the specified scenario (row headings). A dash indicates that …
| Pure 1-sided | 2- sided | 1-sided + 2-sided mix | Semi- diffusive | 1-sided + loading bias | Switching | 1-sided with traversal | 1-sided + 3D attraction | |
|---|---|---|---|---|---|---|---|---|
| Mitosis | No | Yes | Yes with > 80% 2-sided | No | Yes with > 1000 fold bias* | Yes with kswitch/kunbind > 10 | Yes | No |
| Interphase | No | Yes | Yes with > 50% 2-sided | No | Yes with > 100 fold bias | Yes with kswitch/kunbind > 10 | Yes for d ≤ 50 kb or λ > 2 Mb | No** |
| Bacteria | No | Yes | No | No | No | Yes with kswitchL/v > 200 | No | - |
-
**Indicates inferred from simulation results of Fudenberg et al., 2016.
