Heterogeneity and Intrinsic Variation in Spatial Genome Organization

Finn, Elizabeth H.; Pegoraro, Gianluca; Brandão, Hugo B.; Valton, Anne‐Laure; Oomen, Marlies E.; Dekker, Job; Mirny, Leonid A.; Misteli, Tom

doi:10.1101/171801

Cited by 13 publications

(10 citation statements)

References 52 publications

(49 reference statements)

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“…It is clear that there is no dominant cluster, indicating that each Chr5 in single cells is organized differently rather than belonging to a small subset of conformational states. Such large cell-to-cell variations in the structures, without a small number of well defined states, is another hallmark of glasses, which are also revealed in recent experiments (40, 42). The presence of multiple organized structures has profound consequences on the chromosome dynamics (see below).…”

Section: Resultssupporting

confidence: 66%

Interphase Human Chromosome Exhibits Out of Equilibrium Glassy Dynamics

Shi

Liu

Hyeon

et al. 2017

Preprint

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The structural organization of the condensed chromosomes, which hold the secrets to gene regulation, is being revealed using chromosome conformation capture experiments and super resolution imaging techniques. To determine the structure and dynamics of human interphase chromosomes, we created the Chromosome Copolymer Model (CCM) by representing the chromosomes as a self-avoiding polymer with two loci types corresponding to euchromatin and heterochromatin. Using advanced clustering algorithms we establish quantitatively that the simulated contact maps for chromosomes 5 and 10 and those inferred from Hi-C experiments are in agreement. Ward Linkage Matrix (WLM), constructed from spatial distance information, shows that the spatial organization of the Topologically Associating Domains (TADs) and compartments predicted from simulation are in agreement with inferred WLM computed using data from super resolution microscopy experiments. Glassy dynamics is manifested in the stretched exponential relaxation of the structure factor, a pronounced peak in the fourth order susceptibility accounting for the fluctuations in F (k, t), and caging in the mean square displacement of individual loci, ∆ i (t) ∼ t α with 0 < α < 1. Remarkably, the distribution of α, is extremely broad suggestive of highly heterogeneous dynamics. Chromosome folding is hierarchical involving the formation of chromosome droplets (CDs) on short genomic scale followed by coalescence of the CDs, reminiscent of Ostwald ripening. We propose that glassy landscapes for the folded chromosomes might provide a balance between stability and biological functions.

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Section: Resultssupporting

confidence: 66%

Interphase Human Chromosome Exhibits Out of Equilibrium Glassy Dynamics

Shi

Liu

Hyeon

et al. 2017

Preprint

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“…To avoid ambiguity in the context of loop extrusion, we reserve the term "loop" in the narrow sense, for two regions of a continuous chromatin fiber brought together by a LEF at a given point in time. Indeed, simulations (Fudenberg et al 2016;Doyle et al 2014;Hofmann and Heermann 2015;Benedetti et al 2014) and data analyses Finn et al 2017;Cattoni et al 2017;Giorgetti et al 2014) demonstrate that peaks in interphase Hi-C maps are not consistent with stable chromatin loops. Therefore, we refrain from using "loop" to describe any feature of Hi-C contact maps, as they likely emerge from sets of dynamically extruded loops that vary stochastically from cell-to-cell ( Fig.…”

Section: Polymer Model Of Loop Extrusion With Barrier Elementsmentioning

confidence: 99%

Emerging Evidence of Chromosome Folding by Loop Extrusion

Fudenberg

Abdennur

Imakaev

et al. 2018

Preprint

Self Cite

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Chromosome organization poses a remarkable physical problem with many biological consequences: how can molecular interactions between proteins at the nanometer scale organize micron-long chromatinized DNA molecules, insulating or facilitating interactions between specific genomic elements? The mechanism of active loop extrusion holds great promise for explaining interphase and mitotic chromosome folding, yet remains difficult to assay directly. We discuss predictions from our polymer models of loop extrusion with barrier elements, and review recent experimental studies that provide strong support for loop extrusion, focusing on perturbations to CTCF and cohesin assayed via Hi-C in interphase. Finally, we discuss a likely molecular mechanism of loop extrusion by SMC complexes.

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“…Several predictions of the extrusion model have been validated with perturbative Hi-C [ 21 – 25 ] and in vitro experiments [ 26 , 27 ]. Due to its unavoidable ensemble averaging, however, Hi-C cannot capture the heterogeneity within a cell population, and the average picture it presents may be insufficient to uncover the full complexity of genome folding [ 28 , 29 ].…”

Section: Introductionmentioning

confidence: 99%

Characterizing chromatin folding coordinate and landscape with deep learning

Xie

Zhang

2020

PLoS Comput Biol

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Genome organization is critical for setting up the spatial environment of gene transcription, and substantial progress has been made towards its high-resolution characterization. The underlying molecular mechanism for its establishment is much less understood. We applied a deep-learning approach, variational autoencoder (VAE), to analyze the fluctuation and heterogeneity of chromatin structures revealed by single-cell imaging and to identify a reaction coordinate for chromatin folding. This coordinate connects the seemingly random structures observed in individual cohesin-depleted cells as intermediate states along a folding pathway that leads to the formation of topologically associating domains (TAD). We showed that folding into wild-type-like structures remain energetically favorable in cohesin-depleted cells, potentially as a result of the phase separation between the two chromatin segments with active and repressive histone marks. The energetic stabilization, however, is not strong enough to overcome the entropic penalty, leading to the formation of only partially folded structures and the disappearance of TADs from contact maps upon averaging. Our study suggests that machine learning techniques, when combined with rigorous statistical mechanical analysis, are powerful tools for analyzing structural ensembles of chromatin.

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Heterogeneity and Intrinsic Variation in Spatial Genome Organization

Cited by 13 publications

References 52 publications

Interphase Human Chromosome Exhibits Out of Equilibrium Glassy Dynamics

Interphase Human Chromosome Exhibits Out of Equilibrium Glassy Dynamics

Emerging Evidence of Chromosome Folding by Loop Extrusion

Characterizing chromatin folding coordinate and landscape with deep learning

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