Chromatin jets define the properties of cohesin-driven in vivo loop extrusion

Guo, Ya; Al-Jibury, Ediem; Garcia-Millan, Rosalba; Ntagiantas, Konstantinos; King, James W. D.; Nash, Alex J.; Galjart, Niels; Lenhard, Boris; Rueckert, Daniel; Fisher, Amanda G.; Pruessner, Gunnar; Merkenschlager, Matthias

doi:10.1016/j.molcel.2022.09.003

Cited by 34 publications

(49 citation statements)

References 68 publications

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“…These results could explain an observation in recent simulations, which demonstrated that forces exerted by bound molecular motors can bend polymers into hairpins (67). Such zipped structures also arise in Hi-C maps (93)(94)(95) and in our simulated contact maps as jet-like, anti-diagonal features originating from small A regions and extending into the neighboring B compartment [Fig. 2D].…”

supporting

confidence: 86%

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Polymer folding through active processes recreates features of genome organization

Goychuk

Kannan

Chakraborty

et al. 2022

Preprint

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From proteins to chromosomes, polymers fold into specific conformations that control their biological function. Polymer folding has long been studied with equilibrium thermodynamics, yet intracellular organization and regulation involve energy-consuming, active processes. Signatures of activity have been measured in the context of chromatin motion, which shows spatial correlations and enhanced subdiffusion only in the presence of adenosine triphosphate (ATP). Moreover, chromatin motion varies with genomic coordinate, pointing towards a heterogeneous pattern of active processes along the sequence. How do such patterns of activity affect the conformation of a polymer such as chromatin? We address this question by combining analytical theory and simulations to study a polymer subjected to sequence-dependent correlated active forces. Our analysis shows that a local increase in activity (larger active forces) can cause the polymer backbone to bend and expand, while less active segments straighten out and condense. Our simulations further predict that modest activity differences can drive compartmentalization of the polymer consistent with the patterns observed in chromosome conformation capture experiments. Moreover, segments of the polymer that show correlated active (sub)diffusion attract each other through effective long-ranged harmonic interactions, whereas anticorrelations lead to effective repulsions. Thus, our theory offers non-equilibrium mechanisms for forming genomic compartments, which cannot be distinguished from affinity-based folding using structural data alone. As a first step toward disentangling active and passive mechanisms of folding, we discuss a data-driven approach to discern if and how active processes affect genome organization.

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supporting

confidence: 86%

“…2D]. Experiments suggest that these structures could be formed by active loop extrusion (93), which is not explicitly accounted for in our model. Nevertheless, it is interesting that the spontaneous loops induced by a local hot spot of activity could still create jet-like features.…”

Section: Discussionmentioning

confidence: 99%

Polymer folding through active processes recreates features of genome organization

Goychuk

Kannan

Chakraborty

et al. 2022

Preprint

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“…Unless stated otherwise, we assumed that extrusion began at t = 333 s after the start of the recorded simulation trajectories and proceeded at a nominal speed of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{upgreek} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} }{}${V}_0 = 1$\end{document} kb/s ( 17 ). As soon as the extrusion complex reached one of the two anchors, it stopped, and the other side of the chain continued to be extruded unidirectionally ( 18 , 50 , 51 ), at a speed of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{upgreek} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} }{}${{\rm{V}}}_0/2$\end{document} ( 26 ), until the extrusion complex reached the second anchor ( Supplementary Figure S2A ). At this point, extrusion stopped entirely, and the two anchors were maintained in the closed state until the end of the simulation, unless stated otherwise.…”

Section: Resultsmentioning

confidence: 99%

“…The speed of loop extrusion (in base pairs per seconds) is thus defined as \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{upgreek} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} }{}${V}_0 = {\rm{\ }}2g/\Delta t.$\end{document} By default, our simulations assumed that extrusion started at a random location between the beads representing the anchors (extrusion barriers) and proceeded bidirectionally at \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{upgreek} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} }{}$V_0 =$\end{document} 1 kb/s ( 17 , 26 ) until reaching an anchor. Thereafter, loop extrusion proceeded unidirectionally, at the halved speed \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{upgreek} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} }{}$V_0/2{\rm{\ }} = {\rm{\ }}0.5$\end{document} kb/s until reaching the second anchor ( 18 , 50–52 ), whereupon extrusion stopped ( Supplementary Figure S2A ). By default, we then maintained the bond between the two anchor beads until the end of the simulation.…”

Section: Methodsmentioning

confidence: 99%

Polymer simulations guide the detection and quantification of chromatin loop extrusion by imaging

Sabaté

Lelandais

Bertrand

et al. 2023

Nucleic Acids Research

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Genome-wide chromosome conformation capture (Hi-C) has revealed the organization of chromatin into topologically associating domains (TADs) and loops, which are thought to help regulate genome functions. TADs and loops are understood as the result of DNA extrusion mediated by the cohesin complex. However, despite recent efforts, direct visualization and quantification of this process in single cells remains an open challenge. Here, we use polymer simulations and dedicated analysis methods to explore if, and under which conditions, DNA loop extrusion can be detected and quantitatively characterized by imaging pairs of fluorescently labeled loci located near loop or TAD anchors in fixed or living cells. We find that under realistic conditions, extrusion can be detected and the frequency of loop formation can be quantified from fixed cell images alone, while the lifetime of loops and the speed of extrusion can be estimated from dynamic live-cell data. Our delineation of appropriate imaging conditions and the proposed analytical methods lay the groundwork for a systematic quantitative characterization of loop extrusion in fixed or living cells.

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“…S5A). Chromatin jets describe a recently identified Hi-C signature observed at some locally dominant cohesin loading sites that reflect bouquets of unanchored, bi-directionally extruding cohesin molecules that all initiated extrusion at the same site 29 . In contrast, stripes are normally observed at strong CTCF boundaries 12,30 and are believed to reflect differently sized chromatin loops formed by uni-directional extruding cohesin molecules anchored at the same site.…”

Section: Main Textmentioning

confidence: 99%

Targeted cohesin loading characterizes the entry and exit sites of loop extrusion trajectories

Han

Huang

Vaandrager

et al. 2023

Preprint

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The cohesin complex (SMC1-SMC3-RAD21) shapes chromosomes by DNA loop extrusion, but individual extrusion trajectories were so far unappreciable in vivo. Here, we site-specifically induced dozens of extrusion trajectories anchored at artificial loading sites in living cells. Extruding cohesin transports loading proteins MAU2-NIPBL over megabase DNA distances to blocking CTCF sites that then loop back to the loading sequences, showing that CTCF-CTCF interactions are unnecessary for stabilized contacts between loop extrusion obstacles. When stalled, cohesin can block other extruding cohesin from either direction. Without RAD21, MAU2-NIPBL exclusively accumulate at loading sites, here genome-wide defined as enhancers. SMC1 now also selectively accumulates here, suggesting that cohesin may load modularly on chromatin. Genes inside high cohesin extrusion trajectories are collectively hindered in transcription. This work characterizes the impact, entry and exit sites of individual cohesin loop extrusion trajectories.

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Chromatin jets define the properties of cohesin-driven in vivo loop extrusion

Cited by 34 publications

References 68 publications

Polymer folding through active processes recreates features of genome organization

Polymer folding through active processes recreates features of genome organization

Polymer simulations guide the detection and quantification of chromatin loop extrusion by imaging

Targeted cohesin loading characterizes the entry and exit sites of loop extrusion trajectories

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