Cell cycle dynamics of chromosomal organisation at single-cell resolution

Nagano, Takashi; Lubling, Yaniv; Várnai, Csilla; Dudley, C. L.; Leung, Wing-Kit; Baran, Yael; Cohen, Netta Mandelson; Wingett, Steven W.; Fraser, Peter; Tanay, Amos

doi:10.1101/094466

Cited by 18 publications

(23 citation statements)

References 26 publications

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“…TADs are only partially collapsed and interact dynamically with other TADs of the same main epigenomic state. This suggests a substantial stochasticity in chromosome organization, consistent with recent single-cell Hi-C or super-resolution experiments [72][73][74][75][76][77] . We also detected several discrepancies between the predicted and experimental contact maps.…”

Section: /20supporting

confidence: 85%

How epigenome drives chromatin folding and dynamics, insights from efficient coarse-grained models of chromosomes

Ghosh

Jost

2017

Preprint

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The 3D organization of chromosome is crucial for regulating gene expression and cell function. Many experimental and polymer modeling efforts are dedicated to deciphering the mechanistic principles behind chromosome folding. Chromosomes are long and densely packed -topologically constrained -polymers. The main challenge is therefore to develop adequate models and simulation methods to investigate properly the multi spatio-temporal scales of such macromolecules. Here, we develop a generic strategy to develop efficient coarse-grained models for self-avoiding polymers. Accounting accurately for the polymer entanglement length and the volumic density, we show that our simulation scheme not only captures the steadystate structural and dynamical properties of the system but also tracks the same dynamics at different coarse-graining. This strategy allows a strong power-law gain in numerical efficiency and offers a systematic way to define reliable coarse-grained null models for chromosomes and to go beyond the current limitations by studying long chromosomes during an extended time period with good statistics. We use our formalism to investigate in details the time evolution of the 3D organization of chromosome 3R (20 Mbp) in drosophila during one cell cycle (20 hours). We show that a combination of our coarse-graining strategy with a one-parameter block copolymer model integrating epigenomic-driven interactions quantitatively reproduce experimental data at the chromosome-scale and predict that chromatin motion is very dynamic during the cell cycle.

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Section: /20supporting

confidence: 85%

How epigenome drives chromatin folding and dynamics, insights from efficient coarse-grained models of chromosomes

Ghosh

Jost

2017

Preprint

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“…A decade after the first papers about HiC 1 , the techniques to experimentally detect genomic structure at different scales have multiplied. We can now explore 3D chromatin contact dynamics across cell-types 2 , differentiation states 3 , the cell-cycle 4 and even in single-cells 5 .…”

Section: Introductionmentioning

confidence: 99%

GARDEN-NET and ChAseR: a suite of tools for the analysis of chromatin networks

Madrid-Mencía

Raineri

Pancaldi

2019

Preprint

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We introduce an R package and a web-based visualization tool for the representation, analysis and integration of epigenomic data in the context of 3D chromatin interaction networks. GARDEN-NET allows for the projection of user-submitted genomic features on pre-loaded chromatin interaction networks exploiting the functionalities of the ChAseR package to explore the features in combination with chromatin network topology. We demonstrate the approach on epigenomic and chromatin structure datasets in haematopoietic cells.

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“…It has been previously shown that early and late replicating segments observed in population-based replication timing data align with the Hi-C based A and B sub-nuclear compartments respectively 5,6 . A recent study revealed the conservation of the A and B compartments at the single-cell level 27 . The regions of the genome that are replicated at similar times in single-cells align with these compartments demonstrating their structural and functional conservation.…”

Section: Supplementary Figurementioning

confidence: 99%

Single-cell replication profiling reveals stochastic regulation of the mammalian replication-timing program

Dileep¹,

Dm²

2017

Preprint

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In mammalian cells, distinct replication domains (RDs), corresponding to structural units of chromosomes called topologically-associating domains (TADs), replicate at different times during S-phase [1][2][3][4] . Further, early/late replication of RDs corresponds to active/inactive chromatin interaction compartments 5,6 . Although replication origins are selected stochastically, such that each cell is using a different cohort of origins to replicate their genomes [7][8][9][10][11][12] , replication-timing is regulated independently and upstream of origin selection 13 and evidence suggests that replication timing is conserved in consecutive cell cycles 14 . Hence, quantifying the extent of cell-to-cell variation in replication timing is central to studies of chromosome structure and function. Here we devise a strategy to measure variation in single-cell replication timing using DNA copy number. We find that borders between replicated and un-replicated DNA are highly conserved between cells, demarcating active and inactive compartments of the nucleus.Nonetheless, measurable variation was evident. Surprisingly, we detected a similar degree of variation in replication timing from cell-to-cell, between homologues within cells, and between all domains genome-wide regardless of their replication timing.These results demonstrate that stochastic variation in replication timing is independent of elements that dictate timing or extrinsic environmental variation.peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/158352 doi: bioRxiv preprint first posted online Jun. 30, 2017; Dileep and Gilbert, page 3Single-cell DNA copy number can distinguish replicated DNA from un-replicated DNA 15,16 . Specifically, regions that have completed replication will have twice the copy number compared to regions that have not replicated. Hence, we reasoned that measurements of DNA copy number in cells isolated at different times during S-phase could reveal replication-timing programs in single-cells. Moreover, to separately evaluate the extent of extrinsic (cell-to-cell) vs. intrinsic (homologue-to-homologue) variability in replication timing, we examined both haploid H129-2 mouse embryonic stem cells (mESCs) and diploid hybrid musculus 129 × Castaneus mESCs that harbor a high single nucleotide polymorphism (SNP) density between homologues, permitting allele specific analysis. To generate single-cell copy number variation (CNV) profiles, we used flow cytometry of DNA-stained cells to sort single S-phase cells into 96 well plates followed by whole genome amplification (WGA). Amplified DNA from each cell was uniquely barcoded and sequenced (Fig. 1a) 17,18 . To control for amplification and mappability biases, we also sorted G1 and G2 cells, which contain a uniform DNA content. Regions of low mappability and over amplification were removed based on the G1 and G2 controls. Read counts were normalized by dividing the co...

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Cell cycle dynamics of chromosomal organisation at single-cell resolution

Cited by 18 publications

References 26 publications

How epigenome drives chromatin folding and dynamics, insights from efficient coarse-grained models of chromosomes

How epigenome drives chromatin folding and dynamics, insights from efficient coarse-grained models of chromosomes

GARDEN-NET and ChAseR: a suite of tools for the analysis of chromatin networks

Single-cell replication profiling reveals stochastic regulation of the mammalian replication-timing program

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