Theory of chromatin organization maintained by active loop extrusion

Chan, Bernard P.L.; Rubinstein, Michael

doi:10.1073/pnas.2222078120

Cited by 15 publications

(6 citation statements)

References 97 publications

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“…It is anticipated that the ingenious synthesis and precise characterization of high-molecular-weight homopolymer rings , may be extended to create diblock ring polymers and thus propel experimental research on the phase behavior of diblock rings. The study of diblock ring polymer phase behavior could be also stretched to help reflect on the rich features of chromatin organization in the cell nucleus, where abundant loops are present …”

Section: Discussionmentioning

confidence: 99%

Molecular Simulations Revealing Effects of Non-concatenated Ring Topology on Phase Behavior of Symmetric Diblock Copolymers

Wijesekera,

Vigil,

2024

Macromolecules

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The distinctiveness of nonconcatenated ring polymers, as manifested in their fractal globular conformations and selfsimilar dynamics with no long-lived entanglement network, propels the idea of using ring topology to transform the phase behavior of block copolymers. With limited experimental studies of high-molecular-weight diblock ring polymers, large-scale molecular simulations of symmetric diblock copolymers are used to investigate the effects of nonconcatenated ring topology on their phase behavior. The absence of an entanglement network facilitates the phase-separation kinetics, suggesting relative ease in processing diblock ring polymers. The more compact globular conformations of ring polymers with respect to the Gaussian random-walk conformations require a higher enthalpic repulsion to drive the lamellar phase separation. Compared with the mean-field theory for the order−disorder transition in Gaussian diblock ring polymers, the simulations demonstrate the necessity for a new theory incorporating both the effects of fluctuations and the topological invariance of nonconcatenation. In the strong segregation regime, diblock ring polymers are stretched near the lamellar interface but with the globular conformational statistics preserved at larger length scales. The lamellar spacing d increases with enthalpic repulsion between the two blocks as well as the molecular weight of the diblock ring. The scaling argument for d of diblock linear polymers is modified by accounting for the globular conformations and predicts well the dependencies of d on the enthalpic repulsion and molecular weight. The lamellar interface becomes sharper as the enthalpic repulsion increases. While the theory predicts that the intrinsic interfacial width does not depend on the polymer molecular weight or topology, the apparent interfacial width w, which is broadened by the capillary wave, exhibits slight variation with the molecular weight and topology.

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Section: Discussionmentioning

confidence: 99%

Molecular Simulations Revealing Effects of Non-concatenated Ring Topology on Phase Behavior of Symmetric Diblock Copolymers

Wijesekera,

Vigil,

2024

Macromolecules

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“…( 10) and maintaining 𝜆𝜆 ≤ 𝑑𝑑). Indeed, cohesin processivity and separation in mammalian cells are both predicted to be on the order of 200 kbp with limited nesting (7,11,51). The remainder of this work focuses on Regime III.…”

Section: Steady-state Active Loop Extrusion Without Tad Anchors Compa...mentioning

confidence: 99%

“…Separation 𝑑𝑑 is the average genomic length between chromatin-bound cohesins or the inverse of the linear density of cohesins. Both 𝜆𝜆 and 𝑑𝑑 are predicted to be on the order of 200 kbp, suggesting limited loop nesting (7,11,51). Extrusion velocity 𝑣𝑣 𝑒𝑒𝑒𝑒 is the average genomic length extruded per unit time and is equal to the processivity divided by the average residence time of an unobstructed cohesin 𝜏𝜏 𝑟𝑟𝑒𝑒𝑝𝑝 .…”

Section: Introductionmentioning

confidence: 99%

Activity-driven chromatin organization during interphase: compaction, segregation, and entanglement suppression

Chan,

Rubinstein

2024

Preprint

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In mammalian cells, the cohesin protein complex is believed to translocate along chromatin during interphase to form dynamic loops through a process called active loop extrusion. Chromosome conformation capture and imaging experiments have suggested that chromatin adopts a compact structure with limited interpenetration between chromosomes and between chromosomal sections. We developed a theory demonstrating that active loop extrusion causes the apparent fractal dimension of chromatin to cross over between two and four at contour lengths on the order of 30 kilo-base pairs (kbp). The anomalously high fractal dimension D=4 is due to the inability of extruded loops to fully relax during active extrusion. Compaction on longer contour length scales extends within topologically associated domains (TADs), facilitating gene regulation by distal elements. Extrusion-induced compaction segregates TADs such that overlaps between TADs are reduced to less than 35% and increases the entanglement strand of chromatin by up to a factor of 50 to several Mega-base pairs. Furthermore, active loop extrusion couples cohesin motion to chromatin conformations formed by previously extruding cohesins and causes the mean square displacement of chromatin loci during lag times (Δt) longer than tens of minutes to be proportional to Δ t1/3. We validate our results with hybrid molecular dynamics - Monte Carlo simulations and show that our theory is consistent with experimental data. This work provides a theoretical basis for the compact organization of interphase chromatin, explaining the physical reason for TAD segregation and suppression of chromatin entanglements which contribute to efficient gene regulation.

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“…Loop-extrusion models effectively explain TAD formation [13][14][15][16][17][18] . In contrast, copolymer models have been employed to explain the formation of chromatin compartments and the promoter-enhancer interactions 8,[19][20][21][22][23][24] .…”

Section: Introductionmentioning

confidence: 99%

Role of protein-protein interactions on model chromatin organization

Swain,

Choubey,

Vemparala

2024

Preprint

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The three-dimensional organization of chromatin is influenced by DNA-binding proteins, through specific and non-specific interactions. However, the role of DNA sequence and interaction between binding proteins in influencing chromatin structure is not yet fully understood. By employing a simple polymer-based model of chromatin, that explicitly considers sequence-dependent binding of proteins to DNA and protein-protein interactions, we elucidate a mechanism for chromatin organization. We find that: (1) Tuning of protein-protein interaction and protein concentration is sufficient to either promote or inhibit the compartmentalization of chromatin. (2) The presence of chromatin acts as a nucleating site for the condensation of the proteins at a density lower than in isolated protein systems. (3) The exponents describing the spatial distance between the different parts of the chromatin, and their contact probabilities are strongly influenced by both sequence and the protein-protein attraction. Our findings have the potential application of re-interpreting data obtained from various chromosome conformation capture technologies, thereby laying the groundwork for advancing our understanding of chromatin organization.

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Theory of chromatin organization maintained by active loop extrusion

Cited by 15 publications

References 97 publications

Molecular Simulations Revealing Effects of Non-concatenated Ring Topology on Phase Behavior of Symmetric Diblock Copolymers

Molecular Simulations Revealing Effects of Non-concatenated Ring Topology on Phase Behavior of Symmetric Diblock Copolymers

Activity-driven chromatin organization during interphase: compaction, segregation, and entanglement suppression

Role of protein-protein interactions on model chromatin organization

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