Extensive 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:10.1016/j.cell.2019.01.020

Cited by 388 publications

(402 citation statements)

References 80 publications

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“…Accounting for massive heterogeneity in chromosome organization: In a recent study [19], which combined Hi-C and high-throughput optical imaging to map contacts within single chromosomes in human fibroblasts, revealed massive heterogeneity. Such extensive existence of a large number of conformations, leading to multiple or nearly continuous distribution of subpopulations, was much greater than previously anticipated.…”

Section: Resultsmentioning

confidence: 99%

“…4 illustrate. To show that our theory has a broader range of applicability, we used the FISH data from the recent study [19], which reports spatial distance measurements for 212 pairs of loci. We obtained the raw data from the 4D Nu- In Fig.…”

Section: Resultsmentioning

confidence: 99%

“…However, it has been demonstrated using Hi-C and FISH data on the same chromosome that high contact frequency does not always imply proximity in space [13,[15][16][17]. It should be noted that in most cases, the Hi-C and FISH measurements agree very well [8,9,18,19]. However from a purely theoretical perspective even a single contradiction is intriguing if the experimental errors can be ruled out.…”

Section: Introductionmentioning

confidence: 97%

“…By building on the GRMC results, we show that heterogeneity is the dominant feature of chromosome organization. Indeed, recent single-cell Hi-C [20][21][22] and FISH experiments [8,9,18,19] have revealed that there are substantial cell-to-cell variations on genome organization. However, how to utilize the data reported in these experiments to enhance our understanding of 3D genome structural heterogeneity has not been unexplored.…”

Section: Introductionmentioning

confidence: 99%

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Conformational Heterogeneity in Human Interphase Chromosome Organization Reconciles the FISH and Hi-C Paradox

Shi

Thirumalai

2019

Preprint

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Hi-C experiments are used to infer the contact probabilities between loci separated by varying genome lengths. Contact probability should decrease as the spatial distance between two loci increases. However, studies comparing Hi-C and FISH data show that in some cases the distance between one pair of loci, with larger Hi-C readout, is paradoxically larger compared to another pair with a smaller value of the contact probability. We solve the FISH-Hi-C paradox using a theory based on a Generalized Rouse Model for Chromosomes (GRMC).

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Conformational Heterogeneity in Human Interphase Chromosome Organization Reconciles the FISH and Hi-C Paradox

Shi

Thirumalai

2019

Preprint

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“…Most of these studies are based on bulk biochemical assays which can efficiently capture population-level changes in organization or expression but miss out on the cell-to-cell variability within a population. In fact, according to recent reports there is a substantial level of heterogeneity in genome organization within a population and that at a time only a small fraction of cells within a population harbor the interactions captured at the population-level [8,37]. This underscores the need for single cell studies to capture nuclear architecture-dependent regulation of DNA processes in their entirety.…”

Section: Discussionmentioning

confidence: 99%

Investigating the Central Dogma of Molecular Biology in the Context of Nuclear Architecture and Cell Cycle

Dhuppar

Mazumder

2019

Preprint

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Number of figures: 4 Number of characters in the title: 81 Number of words in abstract: 177 Number of words excluding Abstract, Materials and Methods and References: 2498 Number of references: 39 Number of supplementary movies: 1 Number of supplementary Figures: 1 Number of supplementary tables: 1 Abstract Nuclear architecture is the organization of the genome within a cell nucleus with respect to different nuclear landmarks such as nuclear lamina, matrix or nucleoli. Lately it has emerged as a major regulator of gene expression in mammalian cells. The studies connecting nuclear architecture with gene expression are largely population-averaged and do not report on the heterogeneity in genome organization or in gene expression within a population. In this report we present a method for combining 3D DNA Fluorescence in situ Hybridization (FISH) with single molecule RNA FISH (smFISH) and immunofluorescence to study nuclear architecture-dependent gene regulation on a cell-by-cell basis. We further combine it with an imaging-based cell cycle staging to correlate nuclear architecture with gene expression across the cell cycle. We present this in the context of Cyclin A2 (CCNA2) gene for its known cell cycle-dependent expression. We show that, across the cell cycle, the expression of a CCNA2 gene copy is stochastic and depends neither on its sub-nuclear position-which usually lies close to nuclear lamina-nor on the expression from the other copies. Keywords Cell cycle, 3D nuclear architecture, central dogma, DNA FISH, smFISH, Cyclin A2, nuclear lamina, immunofluorescence AM, SD conceived and designed the study. SD performed the experiments and the analysis.AM, SD interpreted the data and wrote the manuscript. AM monitored the project and associated grants. Competing interestsNone.

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How chromosome topologies get their shape: views from proximity ligation and microscopy methods

2020

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The 3D organization of our genome is an important determinant for the transcriptional output of a gene in (patho)physiological contexts. The spatial organization of linear chromosomes within nucleus is dominantly inferred using two distinct approaches, chromosome conformation capture (3C) and DNA fluorescent in situ hybridization (DNA–FISH). While 3C and its derivatives score genomic interaction frequencies based on proximity ligation events, DNA–FISH methods measure physical distances between genomic loci. Despite these approaches probe different characteristics of chromosomal topologies, they provide a coherent picture of how chromosomes are organized in higher‐order structures encompassing chromosome territories, compartments, and topologically associating domains. Yet, at the finer topological level of promoter–enhancer communication, the imaging‐centered and the 3C methods give more divergent and sometimes seemingly paradoxical results. Here, we compare and contrast observations made applying visual DNA–FISH and molecular 3C approaches. We emphasize that the 3C approach, due to its inherently competitive ligation step, measures only ‘relative’ proximities. A 3C interaction enriched between loci, therefore does not necessarily translates into a decrease in absolute spatial distance. Hence, we advocate caution when modeling chromosome conformations.

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Extensive Heterogeneity and Intrinsic Variation in Spatial Genome Organization

Cited by 388 publications

References 80 publications

Conformational Heterogeneity in Human Interphase Chromosome Organization Reconciles the FISH and Hi-C Paradox

Conformational Heterogeneity in Human Interphase Chromosome Organization Reconciles the FISH and Hi-C Paradox

Investigating the Central Dogma of Molecular Biology in the Context of Nuclear Architecture and Cell Cycle

How chromosome topologies get their shape: views from proximity ligation and microscopy methods

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