Differences in the localization and morphology of chromosomes in the human nucleus

doi:10.1083/JCB.145.6.1119

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Differences in the localization and morphology of chromosomes in the human nucleus

Journal Article•DOI•

Differences in the localization and morphology of chromosomes in the human nucleus

Jenny A. Croft¹, Joanna M. Bridger¹, Shelagh Boyle¹, Paul Perry¹, P. W. Teague¹, Wendy A. Bickmore¹ - Show less +2 more•Institutions (1)

Western General Hospital¹

14 Jun 1999-Journal of Cell Biology (Rockefeller University Press)-Vol. 145, Iss: 6, pp 1119-1131

TL;DR: It is demonstrated that the distribution of genomic sequences between chromosomes has implications for nuclear structure and the findings are discussed in relation to a model of the human nucleus that is functionally compartmentalized.

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Abstract: Using fluorescence in situ hybridization we show striking differences in nuclear position, chromosome morphology, and interactions with nuclear substructure for human chromosomes 18 and 19. Human chromosome 19 is shown to adopt a more internal position in the nucleus than chromosome 18 and to be more extensively associated with the nuclear matrix. The more peripheral localization of chromosome 18 is established early in the cell cycle and is maintained thereafter. We show that the preferential localization of chromosomes 18 and 19 in the nucleus is reflected in the orientation of translocation chromosomes in the nucleus. Lastly, we show that the inhibition of transcription can have gross, but reversible, effects on chromosome architecture. Our data demonstrate that the distribution of genomic sequences between chromosomes has implications for nuclear structure and we discuss our findings in relation to a model of the human nucleus that is functionally compartmentalized.

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Journal Article•DOI•

Comprehensive mapping of long-range interactions reveals folding principles of the human genome.

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Erez Lieberman Aiden¹, Nynke L. van Berkum², Louise Williams¹, Maxim Imakaev¹, Tobias Ragoczy³, Tobias Ragoczy⁴, Agnes Telling³, Agnes Telling⁴, Ido Amit¹, Bryan R. Lajoie², Peter J. Sabo⁴, Michael O. Dorschner⁴, Richard Sandstrom⁴, Bradley E. Bernstein¹, Bradley E. Bernstein⁵, Michaël Bender⁴, Mark Groudine⁴, Mark Groudine³, Andreas Gnirke¹, John A. Stamatoyannopoulos⁴, Leonid A. Mirny¹, Eric S. Lander⁵, Eric S. Lander¹, Job Dekker² - Show less +20 more•Institutions (5)

Massachusetts Institute of Technology¹, University of Massachusetts Medical School², Fred Hutchinson Cancer Research Center³, University of Washington⁴, Harvard University⁵

09 Oct 2009-Science

TL;DR: Hi-C is described, a method that probes the three-dimensional architecture of whole genomes by coupling proximity-based ligation with massively parallel sequencing and demonstrates the power of Hi-C to map the dynamic conformations of entire genomes.

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Abstract: We describe Hi-C, a method that probes the three-dimensional architecture of whole genomes by coupling proximity-based ligation with massively parallel sequencing. We constructed spatial proximity maps of the human genome with Hi-C at a resolution of 1 megabase. These maps confirm the presence of chromosome territories and the spatial proximity of small, gene-rich chromosomes. We identified an additional level of genome organization that is characterized by the spatial segregation of open and closed chromatin to form two genome-wide compartments. At the megabase scale, the chromatin conformation is consistent with a fractal globule, a knot-free, polymer conformation that enables maximally dense packing while preserving the ability to easily fold and unfold any genomic locus. The fractal globule is distinct from the more commonly used globular equilibrium model. Our results demonstrate the power of Hi-C to map the dynamic conformations of whole genomes.

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7,180 citations

Journal Article•DOI•

Chromosome territories, nuclear architecture and gene regulation in mammalian cells.

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Thomas Cremer¹, Thomas Cremer², Christoph Cremer¹•Institutions (2)

Heidelberg University¹, Ludwig Maximilian University of Munich²

01 Apr 2001-Nature Reviews Genetics

TL;DR: The emerging view is that chromosomes are compartmentalized into discrete territories and the location of a gene within a chromosome territory seems to influence its access to the machinery responsible for specific nuclear functions, such as transcription and splicing.

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Abstract: The expression of genes is regulated at many levels. Perhaps the area in which least is known is how nuclear organization influences gene expression. Studies of higher-order chromatin arrangements and their dynamic interactions with other nuclear components have been boosted by recent technical advances. The emerging view is that chromosomes are compartmentalized into discrete territories. The location of a gene within a chromosome territory seems to influence its access to the machinery responsible for specific nuclear functions, such as transcription and splicing. This view is consistent with a topological model for gene regulation.

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2,126 citations

Nuclear architecture and gene regulation in mammalian cells

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Christoph Cremer

01 Jan 2001

TL;DR: The emerging view is that chromosomes are compartmentalized into discrete territories, and the location of a gene within a chromosome territory seems to influence its access to the machinery responsible for specific nuclear functions, such as transcription and splicing.

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Abstract: tion of gene expression and other nuclear functions — namely the architecture of the nucleus as a whole. In particular, we describe evidence for a compartmentalized nuclear architecture in the mammalian cell nucleus based on chromosome territories (CTs) and an interchromatin compartment (IC) that contains macromolecular complexes that are required for replication, transcription, splicing and repair (summarized in FIG. 1). Other nuclear components, such as the nucleolus, nuclear lamina and pores, are not reviewed here (for reviews, see REFS 15,16), and although the focus of this review is the mammalian nucleus, the nuclear architecture of other organisms will be mentioned where appropriate. During the past two decades, various new methods have expanded the cell biologist’s ‘toolkit’ for the study of nuclear architecture and function (BOX 1). These methods have provided the basis for detailed studies of CTs, as well as for studies of the topology and dynamics of non-chromatin domains in the nucleus of fixed and, more recently, living cells. Computer simulations of CTs and nuclear architecture are also being used to make quantitative predictions that can be tested experimentally. On the basis of Despite all the celebrations associated with the sequencing of the human genome, and the genomes of other model organisms, our abilities to interpret genome sequences are quite limited. For example, we cannot understand the orchestrated activity — and the silencing — of many thousands of genes in any given cell just on the basis of DNA sequences, such as promoter and enhancer elements. How are the profound differences in gene activities established and maintained in a large number of cell types to ensure the development and functioning of a complex multicellular organism? To answer this question fully, we need to understand how genomes are organized in the nucleus, the basic principles of nuclear architecture and the changes in nuclear organization that occur during cellular differentiation. During recent years, EPIGENETIC mechanisms of gene regulation, such as DNA methylation and histone modification, have entered the centre stage of chromatin research. Modifications of DNA and nucleosomes, however, as well as boundaries and insulators, that affect gene regulation at the chromatin level are not the focus of this article. Instead, we review experimental data and models for a higher level of the regulaCHROMOSOME TERRITORIES, NUCLEAR ARCHITECTURE AND GENE REGULATION IN MAMMALIAN CELLS

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1,984 citations

Cites background from "Differences in the localization and..."

...Although both chromosomes have a similar DNA content (85 and 67 Mb, respectively), the gene-poor chromosome 18 terri-tories were typically found at the nuclear periphery, whereas the gene-rich chromosome 19 territories were located in the nuclear interio...
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Journal Article•DOI•

Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions

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Lars Guelen¹, Ludo Pagie¹, Emilie Brasset, Wouter Meuleman², Wouter Meuleman¹, Marius B. Faza¹, Wendy Talhout¹, Bert H.J. Eussen³, Annelies de Klein³, Lodewyk F. A. Wessels², Lodewyk F. A. Wessels¹, Wouter de Laat, Bas van Steensel¹ - Show less +9 more•Institutions (3)

Netherlands Cancer Institute¹, Delft University of Technology², Erasmus University Rotterdam³

12 Jun 2008-Nature

TL;DR: A high-resolution map of the interaction sites of the entire genome with NL components in human fibroblasts is constructed and demonstrates that the human genome is divided into large, discrete domains that are units of chromosome organization within the nucleus.

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Abstract: The architecture of human chromosomes in interphase nuclei is still largely unknown. Microscopy studies have indicated that specific regions of chromosomes are located in close proximity to the nuclear lamina (NL). This has led to the idea that certain genomic elements may be attached to the NL, which may contribute to the spatial organization of chromosomes inside the nucleus. However, sequences in the human genome that interact with the NL in vivo have not been identified. Here we construct a high-resolution map of the interaction sites of the entire genome with NL components in human fibroblasts. This map shows that genome-lamina interactions occur through more than 1,300 sharply defined large domains 0.1-10 megabases in size. These lamina-associated domains (LADs) are typified by low gene-expression levels, indicating that LADs represent a repressive chromatin environment. The borders of LADs are demarcated by the insulator protein CTCF, by promoters that are oriented away from LADs, or by CpG islands, suggesting possible mechanisms of LAD confinement. Taken together, these results demonstrate that the human genome is divided into large, discrete domains that are units of chromosome organization within the nucleus.

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1,762 citations

Journal Article•DOI•

Nuclear lamins: major factors in the structural organization and function of the nucleus and chromatin

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Thomas Dechat¹, Katrin Pfleghaar¹, Kaushik Sengupta¹, Takeshi Shimi, Dale K. Shumaker, Liliana Solimando¹, Robert D. Goldman - Show less +3 more•Institutions (1)

Northwestern University¹

01 Apr 2008-Genes & Development

TL;DR: An up-to-date overview of the functions of nuclear lamins is provided, emphasizing their roles in epigenetics, chromatin organization, DNA replication, transcription, and DNA repair.

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Abstract: Over the past few years it has become evident that the intermediate filament proteins, the types A and B nuclear lamins, not only provide a structural framework for the nucleus, but are also essential for many aspects of normal nuclear function. Insights into lamin-related functions have been derived from studies of the remarkably large number of disease-causing mutations in the human lamin A gene. This review provides an up-to-date overview of the functions of nuclear lamins, emphasizing their roles in epigenetics, chromatin organization, DNA replication, transcription, and DNA repair. In addition, we discuss recent evidence supporting the importance of lamins in viral infections.

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915 citations

Cites background from "Differences in the localization and..."

...These territories are arranged in a nonrandom fashion, with gene-rich chromosomes, like human chromosome 19, residing preferentially deep inside the nucleus and gene-poor chromosomes, like human chromosome 18, more likely to be positioned in the region of the lamina (Croft et al. 1999)....
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References

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Journal Article•DOI•

Organization of the higher-order chromatin loop: specific DNA attachment sites on nuclear scaffold

[...]

Jovan Mirkovitch¹, Marc-Edouard Mirault¹, Ulrich K. Laemmli¹•Institutions (1)

University of Geneva¹

01 Nov 1984-Cell

TL;DR: Data are presented for sequence-specific chromatin-loop organization in histone-depleted nuclei from Drosophila melanogaster Kc cells and a family of attachment sites related by hybridization to those of the hsp70 genes was discovered.

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1,017 citations

"Differences in the localization and..." refers background in this paper

...The nuclear scaffold and matrix are nuclear substructures that include the lamina, residual nucleoli, and a proteinaceous network pervading the nuclear volume and that are left after extraction of soluble nuclear proteins with the detergent-like salt lithium diiodosalicylate (LIS) or with high salt (Mirkovitch et al., 1984; Luderus et al., 1992)....
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...…that include the lamina, residual nucleoli, and a proteinaceous network pervading the nuclear volume and that are left after extraction of soluble nuclear proteins with the detergent-like salt lithium diiodosalicylate (LIS) or with high salt (Mirkovitch et al., 1984; Luderus et al., 1992)....
[...]

Journal Article•DOI•

Replicon clusters are stable units of chromosome structure: evidence that nuclear organization contributes to the efficient activation and propagation of S phase in human cells.

[...]

Dean A. Jackson¹, Ana Pombo¹•Institutions (1)

University of Oxford¹

23 Mar 1998-Journal of Cell Biology

TL;DR: It is proposed that the coordinated replication of related groups of replicons, that form stable replicon clusters, contributes to the efficient activation and propagation of S phase in mammalian cells.

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Abstract: In proliferating cells, DNA synthesis must be performed with extreme precision. We show that groups of replicons, labeled together as replicon clusters, form stable units of chromosome structure. HeLa cells were labeled with 5-bromodeoxyuridine (BrdU) at different times of S phase. At the onset of S phase, clusters of replicons were activated in each of approximately 750 replication sites. The majority of these replication "foci" were shown to be individual replicon clusters that remained together, as stable cohorts, throughout the following 15 cell cycles. In individual cells, the same replication foci were labeled with BrdU and 5-iododeoxyuridine at the beginning of different cell cycles. In DNA fibers, 95% of replicons in replicon clusters that were labeled at the beginning of one S phase were also labeled at the beginning of the next. This shows that a subset of origins are activated both reliably and efficiently in different cycles. The majority of replication forks activated at the onset of S phase terminated 45-60 min later. During this interval, secondary replicon clusters became active. However, while the activation of early replicons is synchronized at the onset of S phase, different secondary clusters were activated at different times. Nevertheless, replication foci pulse labeled during any short interval of S phase were stable for many cell cycles. We propose that the coordinated replication of related groups of replicons, that form stable replicon clusters, contributes to the efficient activation and propagation of S phase in mammalian cells.

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799 citations

"Differences in the localization and..." refers background in this paper

...Jackson and Pombo (1998) have demonstrated that early replicating DNA is retained within the residual nucleus of salt-extracted human cells and, indeed, the bulk of HSA19 replicates earlier in S phase than does HSA18 (Dutrillaux et al., 1976)....
[...]

Journal Article•DOI•

Association of Transcriptionally Silent Genes with Ikaros Complexes at Centromeric Heterochromatin

[...]

Karen E. Brown¹, Simon Guest¹, Stephen T. Smale², Kyungmin Hahm², Matthias Merkenschlager¹, Amanda G. Fisher¹ - Show less +2 more•Institutions (2)

Imperial College London¹, Howard Hughes Medical Institute²

12 Dec 1997-Cell

TL;DR: It is shown that transcriptionally inactive but not transcriptionally active genes associate with Ikaros-heterochromatin foci, which support a model of organization of the nucleus in which repressed genes are selectively recruited into centromeric domains.

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789 citations

"Differences in the localization and..." refers background in this paper

...The chromosomal and nuclear position of a gene can influence its activity (Brown et al., 1997; Andrulis et al., 1998) and the position of a gene within the nucleus can be dictated by the sequences it is joined to on the chromosome (Csink and Henikoff, 1996; Dernburg et al., 1996)....
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...What are the biological consequences of this type of compartmentalization? The chromosomal and nuclear position of a gene can influence its activity (Brown et al., 1997; Andrulis et al., 1998) and the position of a gene within the nucleus can be dictated by the sequences it is joined to on the chromosome (Csink and Henikoff, 1996; Dernburg et al....
[...]
...Specific parts of chromosomes may adopt different orientations during the cell cycle (Ferguson and Ward, 1992; Vourc’h et al., 1993; Brown et al., 1997; Csink and Henikoff, 1998; Li et al., 1998), but it was not known whether entire mammalian chromosomes move or change their state of condensation....
[...]
...Specific parts of chromosomes may adopt different orientations during the cell cycle (Ferguson and Ward, 1992; Vourc’h et al., 1993; Brown et al., 1997; Csink and Henikoff, 1998; Li et al., 1998), but it was not known whether entire mammalian chromosomes move or change their state of condensation....
[...]

Journal Article•DOI•

The inactive X chromosome in female mammals is distinguished by a lack of histone H4 acetylation, a cytogenetic marker for gene expression

[...]

Peter Jeppesen¹, Bryan M. Turner²•Institutions (2)

Western General Hospital¹, University of Birmingham²

30 Jul 1993-Cell

TL;DR: In this paper, immunolabeled human and mouse metaphase chromosomes with antibodies specific for the acetylated isoforms of histone H4 were labeled in regions corresponding to conventional R bands (regions enriched in coding DNA), except for a single chromosome in female cells.

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711 citations

Journal Article•DOI•

A Physical Map of 30,000 Human Genes

[...]

Panos Deloukas, Gregory D. Schuler¹, G. Gyapay¹, E. M. Beasley¹, Carol Soderlund¹, P. Rodriguez-Tomé¹, L. Hui¹, Tara C. Matise¹, K. B. McKusick¹, Jacques S. Beckmann¹, S. Bentolila¹, M.-T. Bihoreau¹, B. B. Birren¹, J. Browne¹, Adam Butler¹, A. B. Castle¹, N. Chiannilkulchai¹, C. Clee¹, P. J. R. Day¹, Anindya Dehejia¹, T. Dibling¹, N. Drouot¹, S. Duprat¹, C. Fizames¹, Sidney W. Fox¹, S. Gelling¹, L. Green¹, Paul Harrison¹, R. Hocking¹, E. Holloway¹, Sarah E. Hunt¹, S. Keil¹, Philip Lijnzaad¹, C. Louis-Dit-Sully¹, Jianpeng Ma¹, A. Mendis¹, J.H. Miller¹, J. Morissette¹, D. Muselet¹, H. C. Nusbaum¹, A. Peck¹, Steve Rozen¹, D. Simon¹, Donna K. Slonim¹, R. Staples¹, L. D. Stein¹, E. A. Stewart¹, Marc A. Suchard¹, T. Thangarajah¹, N. Vega-Czarny¹, Caleb Webber¹, Xufeng S. Wu¹, James R. Hudson¹, Charles Auffray¹, N. Nomura¹, James M. Sikela¹, Mihael H. Polymeropoulos¹, M. R. James¹, Eric S. Lander¹, Thomas J. Hudson¹, Richard M. Myers¹, D. R. Cox¹, Jean Weissenbach¹, Mark S. Boguski¹, D. R. Bentley¹ - Show less +61 more•Institutions (1)

National Institutes of Health¹

23 Oct 1998-Science

TL;DR: A map of 30,181 human gene-based markers was assembled and integrated with the current genetic map by radiation hybrid mapping, which contains nearly twice as many genes as the previous release and is twofold to threefold more accurate than the previous version.

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Abstract: A map of 30,181 human gene-based markers was assembled and integrated with the current genetic map by radiation hybrid mapping. The new gene map contains nearly twice as many genes as the previous release, includes most genes that encode proteins of known function, and is twofold to threefold more accurate than the previous version. A redesigned, more informative and functional World Wide Web site (www.ncbi.nlm.nih.gov/genemap) provides the mapping information and associated data and annotations. This resource constitutes an important infrastructure and tool for the study of complex genetic traits, the positional cloning of disease genes, the cross-referencing of mammalian genomes, and validated human transcribed sequences for large-scale studies of gene expression.

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679 citations

"Differences in the localization and..." refers background or result in this paper

...In contrast, HSA18 has far fewer gene assignments than expected for its size (Cross et al., 1997; Deloukas et al., 1998), with only 1.7% of gene-based markers mapped to it....
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...The number of gene-based markers that has been assigned to HSA18 is small in comparison to those located on HSA19 (Craig and Bickmore, 1994; Deloukas et al., 1998)....
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...In contrast, HSA18 has far fewer gene assignments than expected for its size (Cross et al., 1997; Deloukas et al., 1998), with only 1....
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...HSA19 also has the highest observed/ expected ratio of gene-based marker assignments of any human autosome (Cross et al., 1997; Deloukas et al., 1998) with 3.7% of such markers assigned to it....
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...HSA19 also has the highest observed/ expected ratio of gene-based marker assignments of any human autosome (Cross et al., 1997; Deloukas et al., 1998) with 3....
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