Effective model of loop extrusion predicts chromosomal domains

Crippa, Martina; Zhan, Yinxiu; Tiana, Guido

doi:10.1103/physreve.102.032414

Cited by 10 publications

(14 citation statements)

References 34 publications

(51 reference statements)

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“…The extrusion process halts in correspondence with specific blocking anchors, i.e., convergently-oriented CTCF binding sites, which mark the boundaries of consecutive genomic regions [ 61 , 62 ]. In different variants of the model, the extruding complexes are subject, for instance, to passive diffusion [ 91 ] or pushed, e.g., by transcription-induced supercoiling [ 84 ], or their positions along the chain are averaged out in order to build effective equilibrium models consistent with explicit-extruder approaches [ 96 ]. Polymer simulations based on LE have been used to explain, for example, the formation and compaction of mitotic chromosomes [ 97 ], organization of TADs in interphase [ 61 , 62 ], or the structural effects of CTCF/cohesin degradation at the cell population-average level [ 73 , 98 ].…”

Section: Resultsmentioning

confidence: 99%

Unveiling the Machinery behind Chromosome Folding by Polymer Physics Modeling

Conte

Esposito

Vercellone

et al. 2023

IJMS

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Understanding the mechanisms underlying the complex 3D architecture of mammalian genomes poses, at a more fundamental level, the problem of how two or multiple genomic sites can establish physical contacts in the nucleus of the cells. Beyond stochastic and fleeting encounters related to the polymeric nature of chromatin, experiments have revealed specific, privileged patterns of interactions that suggest the existence of basic organizing principles of folding. In this review, we focus on two major and recently proposed physical processes of chromatin organization: loop-extrusion and polymer phase-separation, both supported by increasing experimental evidence. We discuss their implementation into polymer physics models, which we test against available single-cell super-resolution imaging data, showing that both mechanisms can cooperate to shape chromatin structure at the single-molecule level. Next, by exploiting the comprehension of the underlying molecular mechanisms, we illustrate how such polymer models can be used as powerful tools to make predictions in silico that can complement experiments in understanding genome folding. To this aim, we focus on recent key applications, such as the prediction of chromatin structure rearrangements upon disease-associated mutations and the identification of the putative chromatin organizing factors that orchestrate the specificity of DNA regulatory contacts genome-wide.

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Section: Resultsmentioning

confidence: 99%

Unveiling the Machinery behind Chromosome Folding by Polymer Physics Modeling

Conte

Esposito

Vercellone

et al. 2023

IJMS

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“…Chromatin fibres are modelled as bead-and-spring polymers [9,11,12,[29][30][31][32][33][34][35][36][37][38], where each monomer (diameter σ) represents 3 kbp packed into a 30 nm sphere [9,11,35]. Different TFs (or TF:pol complexes) are modelled as differently-coloured spheres (also with diameter σ) able to bind (when in an "on" state) to cognate sites of the same colour that are scattered along the polymer.…”

Section: Methodsmentioning

confidence: 99%

A multicolour polymer model for the prediction of 3D structure and transcription in human chromatin

Semeraro

Negro

Suma

et al. 2023

Preprint

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Within each human cell, different kinds of RNA polymerases and a panoply of transcription factors bind chromatin to simultaneously determine 3D chromosome structure and transcriptional programme. Experiments show that, in some cases, different proteins segregate to form specialised transcription factories; in others they mix together, binding promiscuously the same chromatin stretch. Here, we use Brownian dynamics simulations to study a polymer model for chromosomes accounting for multiple types ('colours') of chromatin-binding proteins. Our multi-colour model shows the spontaneous emergence of both segregated and mixed clusters of chromatin bound proteins, depending mainly on their size, thereby reconciling the previous experimental observations. Additionally, remarkable small-world networks emerge; in these, positive and negative correlations in activities of transcription units provide simple explanations of why adjacent units in large domains are co-transcribed so often, and how one eQTL (expression quantitative trait locus) can up-regulate some genes and down-regulate others. We also explain how local genome edits induce distant om- nigenic and pangenomic effects, and develop ways to predict activities of all transcription units on human chromosomes. All results point to 1D location being a key determinant of transcription, consistently with the conservation of synteny seen between rapidly-evolving enhancers and their more stable target genes.

show abstract

Section: Methodsmentioning

confidence: 99%

A multicolour polymer model for the prediction of 3D structure and transcription in human chromatin

Semeraro¹,

Negro²,

Suma³

et al. 2023

Preprint

View full text Add to dashboard Cite

Within each human cell, different kinds of RNA polymerases and a panoply of transcription factors bind chromatin to simultaneously determine 3D chromosome structure and transcriptional programme. Experiments show that, in some cases, different proteins segregate to form specialised transcription factories; in others they mix together, binding promiscuously the same chromatin stretch. Here, we use Brownian dynamics simulations to study a polymer model for chromosomes accounting for multiple types ("colours") of chromatin-binding proteins. Our multi-colour model shows the spontaneous emergence of both segregated and mixed clusters of chromatin-bound proteins, depending mainly on their size, thereby reconciling the previous experimental observations. Additionally, remarkable small-world networks emerge; in these, positive and negative correlations in activities of transcription units provide simple explanations of why adjacent units in large domains are co-transcribed so often, and how one eQTL (expression quantitative trait locus) can up-regulate some genes and down-regulate others. We also explain how local genome edits induce distant omnigenic and pangenomic effects, and develop ways to predict activities of all transcription units on human chromosomes. All results point to 1D location being a key determinant of transcription, consistently with the conservation of synteny seen between rapidly-evolving enhancers and their more stable target genes.

show abstract

Effective model of loop extrusion predicts chromosomal domains

Cited by 10 publications

References 34 publications

Unveiling the Machinery behind Chromosome Folding by Polymer Physics Modeling

Unveiling the Machinery behind Chromosome Folding by Polymer Physics Modeling

A multicolour polymer model for the prediction of 3D structure and transcription in human chromatin

A multicolour polymer model for the prediction of 3D structure and transcription in human chromatin

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