A minimal Gō-model for rebuilding whole genome structures from haploid single-cell Hi-C data

Wettermann, Sarah; Brems, Maarten A.; Siebert, J.; Vu, Giang T. H.; Stevens, Tim J.; Virnau, Peter

doi:10.1016/j.commatsci.2019.109178

Cited by 9 publications

(20 citation statements)

References 54 publications

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“…Therefore, if there were chromatin knots with cores smaller than 150 kb, they would not produce knotted parts of polygonal tracings and thus would be missed. However, this compares favourably, though, with single cell Hi-C modelling approach, which due to its 100 kb resolution (24)(25)(26)(27), can't detect chromatin knots if they would be even as large as 500 kb. On the other end of the scale, if the knot core would be larger than 2 Mb (size of analysed fragments), we would also miss it in our analysis.…”

Section: Discussionmentioning

confidence: 95%

“…For this reason, all possible chromatin knots which were not spread over a chromatin portion larger than 500 kb could only form unknotted portions of the polygonal chain representing a given chromosome modelled at 100 kb resolution. In fact, the reproducibly observed trefoil knot in modelling studies based on single cell Hi-C data was spread over 25 segments, which corresponds to 2.5 Mb large chromatin portion (24,27).…”

Section: Introductionmentioning

confidence: 97%

“…Previous methods of population Hi-C could only give an information about the average path of chromatin fibres constituting a given chromosome in millions of cells of a given type (5,21,22) and since chromosomes are highly dynamic (23) one could not use the population HI-C data to search for chromatin knots in individual chromosomes. Very recent studies using numerical simulations to analyse single cell Hi-C data suggested that chromatin fibres in individual chromosomes can be knotted (24)(25)(26)(27). However, the concluded knotting level was low with just one trefoil knot that appeared consistently in independent numerical simulations starting from the same single cell Hi-C data of human chromosome 14 (27).…”

Section: Introductionmentioning

confidence: 99%

“…Very recent studies using numerical simulations to analyse single cell Hi-C data suggested that chromatin fibres in individual chromosomes can be knotted (24)(25)(26)(27). However, the concluded knotting level was low with just one trefoil knot that appeared consistently in independent numerical simulations starting from the same single cell Hi-C data of human chromosome 14 (27). However, the apparent paucity of chromatin knots concluded from single cell Hi-C data may be the consequence of unavoidable low resolution of single-cell Hi-C approach that currently does not exceed 100 kb (20).…”

Section: Introductionmentioning

confidence: 99%

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Chromatin is frequently unknotted at the megabase scale

Goundaroulis

Aiden

Stasiak

2019

Preprint

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Knots in the human genome would greatly impact diverse cellular processes ranging from transcription to gene regulation. To date, it has not been possible to directly examine the genome in vivo for the presence of knots. Recently, methods for serial fluorescent in situ hybridization have made it possible to measure the 3d position of dozens of consecutive genomic loci, in vivo. However, the determination of whether genomic trajectories are knotted remains challenging, because small errors in the localization of a single locus can transform an unknotted trajectory into a highlyknotted trajectory, and vice versa. Here, we use stochastic closure analysis to determine whether a genomic trajectory is knotted in the setting of experimental noise. We analyse 4727 deposited genomic trajectories of a 2Mb long chromatin interval from chromosome 21. For 243 of these trajectories, their knottedness could be reliably determined despite the possibility of localization errors. Strikingly, in each of these 243 cases, the trajectory was unknotted. We note a potential source of bias, insofar as knotted contours may be more difficult to reliably resolve. Nevertheless, our data is consistent with a model where, at the scales probed, the human genome is often free of knots.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Chromatin is frequently unknotted at the megabase scale

Goundaroulis

Aiden

Stasiak

2019

Preprint

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show abstract

“…Many approaches have been developed to reconstruct the 3D folding of individual chromosomes and the genome from Hi-C data at different resolutions using restraint and polymer physics based approaches [40,41]. Some models focus on detailed structures of local regions of chromatin rather than the whole genome, and for others, the primary focus is often to understand the mechanistic principles underlying the organization of interphase and metaphase genome rather than a prediction of CT arrangement [42,43,44,45,46,47,48]. But, some of the approaches have also explored the radial arrangement of CTs in their 3D models.…”

Section: Introductionmentioning

confidence: 99%

Inferring Chromosome Radial Organization from Hi-C Data

Das

Shen

McCord

2019

Preprint

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AbstractBackgroundThe nonrandom radial organization of eukaryotic chromosome territories (CTs) inside the nucleus plays an important role in nuclear functional compartmentalization. Increasingly, chromosome conformation capture (Hi-C) based approaches are being used to characterize the genome structure of many cell types and conditions. Computational methods to extract 3D arrangements of CTs from this type of pairwise contact data will thus increase our ability to analyze CT organization in a wider variety of biological situations.ResultsA number of full-scale polymer models have successfully reconstructed the 3D structure of chromosome territories from Hi-C. To supplement such methods, we explore alternative, direct, and less computationally intensive approaches to capture radial CT organization from Hi-C data. We show that we can infer relative chromo-some ordering using PCA on a thresholded inter-chromosomal contact matrix. We simulate an ensemble of possible CT arrangements using a force-directed network layout algorithm and propose an approach to integrate additional chromosome properties into our predictions. Our CT radial organization predictions have a high correlation with microscopy imaging data for various cell nucleus geometries (lymphoblastoid, skin fibroblast, and breast epithelial cells), and we can capture previously documented changes in senescent and progeria cells.ConclusionsOur analysis approaches provide rapid and modular approaches to screen for alterations in CT organization across widely available Hi-C data. We demon-strate which stages of the approach can extract meaningful information, and also de-scribe limitations of pairwise contacts alone to predict absolute 3D positions.

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Chromatin Is Frequently Unknotted at the Megabase Scale

Goundaroulis

Aiden

Stasiak

2020

Biophysical Journal

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Knots in the human genome would greatly impact diverse cellular processes ranging from transcription to gene regulation. To date, it has not been possible to directly examine the genome in vivo for the presence of knots. Recently, methods for serial fluorescent in situ hybridization have made it possible to measure the three-dimensional position of dozens of consecutive genomic loci in vivo. However, the determination of whether genomic trajectories are knotted remains challenging because small errors in the localization of a single locus can transform an unknotted trajectory into a highly knotted trajectory and vice versa. Here, we use stochastic closure analysis to determine if a genomic trajectory is knotted in the setting of experimental noise. We analyze 4727 deposited genomic trajectories of a 2-Mb-long chromatin interval from human chromosome 21. For 243 of these trajectories, their knottedness could be reliably determined despite the possibility of localization errors. Strikingly, in each of these 243 cases, the trajectory was unknotted. We note a potential source of bias insofar as knotted contours may be more difficult to reliably resolve. Nevertheless, our data are consistent with a model in which, at the scales probed, the human genome is often free of knots.

show abstract

A minimal Gō-model for rebuilding whole genome structures from haploid single-cell Hi-C data

Cited by 9 publications

References 54 publications

Chromatin is frequently unknotted at the megabase scale

Chromatin is frequently unknotted at the megabase scale

Inferring Chromosome Radial Organization from Hi-C Data

Chromatin Is Frequently Unknotted at the Megabase Scale

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