Where Does the Genome Live?

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According to Meaburn and Misteli, the natural habitat of eukaryotic genomes is the cell nucleus, where each chromosome is confined to a discrete region termed a chromosome territory, the spatial organization of which may play a crucial role in gene regulation and genome stability in both health and disease. This paper explores a number of new, at least to most of us, concepts relevant to chromosome structure, organization and function.

Chromosome territories as visualized in vivo by fluorescent tags that distinguish the different chromosomes are roughly spherical domains of about 2 microns in diameter that occupy the nucleus (Figure 1). The interiors of the territories are permeated by highly branched, interconnected networks of channels that make the genome sequences deep inside accessible to regulatory factors such as transcriptional activators and repressors.

Figure 1

Spatial organization in the nucleus. (a) Territories can be visualized using chromosome-specific fluorescent probes. In this mouse liver nucleus, chromosome 12 (red), chromosome 14 (green) and chromosome 15 (blue) were painted. (b) Modern imaging techniques allow all chromosomes in a cell to be visualized simultaneously, as seen here in a human fibroblast. (c) Chromosome territories are not solid entities, and their interior is permeated by a network of nucleoplasmic channels. (d–f) Higher-order organization of chromosome territories. In plants, the chromatin fiber forms a rosette-like structure (d), whereas in higher eukaryotes chromatin forms interconnected megabase-sized domains (e). Other models suggest looping of the fiber from a central backbone (f). Reprinted with permission: Meaburn KJ, Misteli T. Nature. 2007;445:379-81. Copyright © NPG 2007. All rights reserved.

The structural organization within territories is not random, with chromosome arms mostly kept apart from one another and gene-rich chromosome regions separated from gene-poor regions. Chromosome fibers comprised of DNA and associated proteins appear to form loops of different sizes that are anchored to each other at their bases. Loops from one chromosome may sometimes protrude into the territory of a neighboring chromosome and intermingle with its fibers.

Chromosome territories seem to be arranged radially so that each chromosome is assigned a preferential location relative to the nuclear center with certain chromosomes, tending to be located in the interior, and others at the nuclear edge. A consequence of this arrangement is that chromosomes often reside in preferred clusters of neighboring chromosomes. Although a chromosome may occupy a preferential place in a population of cells, it may vary within individual cells. Chromosomal arrangements are also specific to different cell and tissue types and can change during differentiation and development (Figure 2). Interestingly, although territorial arrangements are lost during mitosis, chromosomes seem to find the same relative position in daughter cells that they occupied in the parental cells.

Figure 2

Arrangement of chromosome territories. a, Chromosomes occupy nonrandom radial positions relative to the centre of the nucleus. Red and orange chromosomes are preferentially internal, green chromosomes intermediate and blue chromosomes peripheral. Positioning patterns are probabilistic, and preferential radial positions lead to nonrandom clusters of chromosomes. b, Changing the relative arrangement of genome regions (coloured rectangles) to bring them into close proximity is functionally relevant for gene activity, and for the formation of chromosomal translocations. Reprinted with permission: Meaburn KJ, Misteli T. Cell biology:chromosome territories. Nature. 2007;445:379-81.

The authors suggested that this nonrandom spatial organization of chromosomes allows for functional compartmentalization. This would allow active and inactive genome regions to be separated from each other. It would also potentially bring co-regulated genes into physical proximity to coordinate their expression.

How chromosomes find their place in the nucleus is not known. Two mechanisms have been proposed. The first is that chromosomal positions may be determined through their associations with immobile nuclear elements, ie, nuclear scaffold. It is difficult to explain nonrandom positioning and especially changes with cellular behaviors by this mechanism. The second mechanism involves a self-organizing model in which chromosome position is determined by the activity of a chromosome’s genes. This model could explain clustering of active and inactive chromosomal regions and variation in different cell and tissue types.

The position of chromosomal regions within a nucleus may influence expression of genes in these regions. The actual position of a gene probably does not determine if a gene is expressed or not, but more likely modulates its level of expression, perhaps to optimize its expression. This may occur because regulatory elements are brought in close proximity to otherwise distant genes.

Chromosome position may have implications for genome stability. For instance, chromosomes that are preferentially close to one another are more likely to undergo translocation than chromosomes that are far apart. It may also have implications for imprinting.

Finally, the authors suggested that there is potential diagnostic relevance to chromosome territories. It is possible that a disease process could lead to a characteristic change of a genomic region’s nuclear position. If this could be easily detected, it could be used as a diagnostic test and also to quickly distinguish diseased cells from non-diseased cells.

Meaburn KJ, Misteli T. Cell biology:chromosome territories. Nature. 2007;445:379-81.

Editor’s Comment

This is a very enlightening review that should bring up to date readers of GGH who are not cytogeneticists but who would like to learn more about the functional organization of the nucleus and how this knowledge might be utilized in a medical setting.

William A. Horton, MD

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Last Updated: 04/30/2008