Polymer physics of chromosome large-scale 3D organisation

Chiariello, Andrea M.; Annunziatella, Carlo; Bianco, Simona; Esposito, Andrea; Nicodemi, Mario

doi:10.1038/srep29775

Cited by 186 publications

(309 citation statements)

References 29 publications

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“…However, these data do not distinguish between CTCF-mediated loops and other contacts, which may either form stochastically or through other chromatin-binding proteins [31][32][33][34]. Chromatin…”

Section: A Single Slip-link 1d Modelmentioning

confidence: 99%

Nonequilibrium Chromosome Looping via Molecular Slip Links

et al. 2017

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We propose a model for the formation of chromatin loops based on the diffusive sliding of a DNA-bound factor which can dimerise to form a molecular slip-link. Our slip-links mimic the behaviour of cohesin-like molecules, which, along with the CTCF protein, stabilize loops which organize the genome. By combining 3D Brownian dynamics simulations and 1D exactly solvable non-equilibrium models, we show that diffusive sliding is sufficient to account for the strong bias in favour of convergent CTCF-mediated chromosome loops observed experimentally. Importantly, our model does not require any underlying, and energetically costly, motor activity of cohesin. We also find that the diffusive motion of multiple slip-links along chromatin may be rectified by an intriguing ratchet effect that arises if slip-links bind to the chromatin at a preferred "loading site". This emergent collective behaviour is driven by a 1D osmotic pressure which is set up near the loading point, and favours the extrusion of loops which are much larger than the ones formed by single slip-links.1 arXiv:1612.07256v1 [physics.bio-ph] Dec 2016The formation of long-range contacts, or loops, within DNA and chromosomes is a process which critically affects gene expression [1, 2]. For instance, looping between specific regulatory elements, such as enhancers and promoters, can dramatically increase transcription rates in eukaryotes [1]. The formation of these loops can often be successfully predicted by equilibrium polymer physics models, which balance the energetic gain of protein-mediated interactions with the entropic loss associated with loop formation [3][4][5].However, recent high-throughput chromosome conformation capture ("Hi-C") experiments [6, 7] have fundamentally challenged the view that equilibrium physics is sufficient to model chromosome looping. Hi-C experiments showed that the genomes of most eukaryotic organisms are partitioned into domains -called "topologically associated domains", or TADs. In several cases, these domains were found to be enclosed within a chromosome loop, 100 − 1000 kilo-basepairs (kpb) in size, and the bases of the loops are statistically enriched in binding sites for the CCCTC-binding factor (CTCF) [7, 8]. CTCF is a DNA-binding protein with an important role in gene regulation, and CTCF-mediated loops preferentially enclose inducible genes, which are normally silent and are pressed into action in response to a stimulus (e.g., an inflammation or an increased concentration of a morphogen during development) [8]. The DNA-binding motif of CTCF is not palindromic, meaning that it has a specific direction on the DNA. Surprisingly, Hi-C analyses have recently revealed that most of the CTCF binding sequences only form a loop when they are in a "convergent" orientation ( Fig. 1a) [7, 10]. Very few contacting CTCFs have a "parallel" orientation, and virtually none have a "divergent" one. This strong bias is puzzling, because, if we imagine drawing arrows on the chromatin fiber (corresponding to the CTCF binding site...

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Section: A Single Slip-link 1d Modelmentioning

confidence: 99%

Nonequilibrium Chromosome Looping via Molecular Slip Links

et al. 2017

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“…В свою очередь, двухмерная карта (симметричная матрица) контактов участков (звеньев) последовательности позволяет реконструировать трёхмерную укладку [11]. Основной технической Организация пространственной структуры хромосом, их укладки в интерфазном ядре клетки, установление взаимодействующих участков генома эукариот, физически контактирующих друг с другом, активно изучается в мире с использованием современных технологий секвенирования.…”

Section: карты хромосомных контактов и сравнение технологийunclassified

“…Рассматриваются вопросы формирования топологических доменов, выделения петель, формируемых контактами когезина и фактора CTCF [10]. Для обработки большого объёма данных ChIA-PET и Hi-C, развиваются компьютерные инструменты анализа, позволяющие получить качественно новую информацию о различных аспектах структурной организации генома [11].…”

Section: Introductionunclassified

Computer methods of analysis of chromosome contacts in the cell nucleus based on sequencing technology data

et al. 2017

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The study spatial chromosome structure and chromosome folding in the interphase cell nucleus is an important challenge of world science. Detection of eukaryotic genome regions that physically interact with each other could be done by modern sequencing technologies. A basic method of chromosome folding by total sequencing of contacting DNA fragments is HI-C. Long-range chromosomal interactions play an important role in gene transcription and regulation. The study of chromosome interactions, 3D (three-dimensional) genome structure and its effect on gene transcription allows revealing fundamental biological processes from a viewpoint of structural regulation and are important for cancer research. The technique of chromatin immunoprecipitation and subsequent sequencing (ChIP-seq) make possible to determine binding sites of transcription factors that regulate expression of eukaryotic genes; genome transcription factors binding maps have been. The ChIA-PET technology allows exploring not only target protein binding sites, but also pairs of such sites on proximally located and interacting with each other chromosomes co-located in three-dimensional space of the cell nucleus. Here we discuss the principles of the construction of genomic maps and matrices of chromosome contacts according to ChIA-PET and Hi-C data that capture the chromosome conformation and overview existing software for 3D genome analysis including in house programs of gene location analysis in topological domains.

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“…It is made available under a The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/095992 doi: bioRxiv preprint first posted online Dec. 21, 2016; data do not distinguish between CTCF-mediated loops and other contacts, which may either form stochastically or through other chromatin-binding proteins [31][32][33][34]. Chromatin Interaction Analysis by Paired-End Tag Sequencing (ChIA-PET) experiments [9] are able to single out contacts where both anchor points are bound to a protein of interest.…”

mentioning

confidence: 99%

“…Furthermore, we envisage that high-throughput (e.g., ChIA-PET) experiments probing the looping probabilities controlled by different loopmediating proteins (such as PolII) will also help illuminate general non-equilibrium features of loop formation in chromosomes. Finally, from a theoretical point of view, it would be of interest to study the behaviour of chromatin fibers subject to both molecular slip-links and more conventional bridging and writing proteins, such as those considered in [31][32][33][34]37]. …”

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confidence: 99%

Non-equilibrium chromosome looping via molecular slip-links

Brackley

Johnson

Michieletto

et al. 2016

Preprint

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We propose a model for the formation of chromatin loops based on the diffusive sliding of a DNA-bound factor which can dimerise to form a molecular slip-link. Our slip-links mimic the behaviour of cohesin-like molecules, which, along with the CTCF protein, stabilize loops which organize the genome. By combining 3D Brownian dynamics simulations and 1D exactly solvable non-equilibrium models, we show that diffusive sliding is sufficient to account for the strong bias in favour of convergent CTCF-mediated chromosome loops observed experimentally. Importantly, our model does not require any underlying, and energetically costly, motor activity of cohesin. We also find that the diffusive motion of multiple slip-links along chromatin may be rectified by an intriguing ratchet effect that arises if slip-links bind to the chromatin at a preferred "loading site". This emergent collective behaviour is driven by a 1D osmotic pressure which is set up near the loading point, and favours the extrusion of loops which are much larger than the ones formed by single slip-links. 1. CC-BY 4.0 International license not peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/095992 doi: bioRxiv preprint first posted online Dec. 21, 2016; The formation of long-range contacts, or loops, within DNA and chromosomes is a process which critically affects gene expression [1,2]. For instance, looping between specific regulatory elements, such as enhancers and promoters, can dramatically increase transcription rates in eukaryotes [1]. The formation of these loops can often be successfully predicted by equilibrium polymer physics models, which balance the energetic gain of protein-mediated interactions with the entropic loss associated with loop formation [3][4][5].However, recent high-throughput chromosome conformation capture ("Hi-C") experiments [6, 7] have fundamentally challenged the view that equilibrium physics is sufficient to model chromosome looping. Hi-C experiments showed that the genomes of most eukaryotic organisms are partitioned into domains -called "topologically associated domains", or TADs. In several cases, these domains were found to be enclosed within a chromosome loop, 100 − 1000 kilo-basepairs (kpb) in size, and the bases of the loops are statistically enriched in binding sites for the CCCTC-binding factor (CTCF) [7, 8]. CTCF is a DNA-binding protein with an important role in gene regulation, and CTCF-mediated loops preferentially enclose inducible genes, which are normally silent and are pressed into action in response to a stimulus (e.g., an inflammation or an increased concentration of a morphogen during development) [9]. The DNA-binding motif of CTCF is not palindromic, meaning that it has a specific direction on the DNA. Surprisingly, Hi-C analyses have recently revealed that most of the CTCF binding sequences only form a loop when they are in a "convergent" orientation ( Fig. 1a) [7, 10]. Very few contacting CTCFs ha...

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Polymer physics of chromosome large-scale 3D organisation

Cited by 186 publications

References 29 publications

Nonequilibrium Chromosome Looping via Molecular Slip Links

Nonequilibrium Chromosome Looping via Molecular Slip Links

Computer methods of analysis of chromosome contacts in the cell nucleus based on sequencing technology data

Non-equilibrium chromosome looping via molecular slip-links

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