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Chromosome Territories Downloaded from http://cshperspectives.cshlp.org/ on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press Chromosome Territories Thomas Cremer1,2 and Marion Cremer1 1Biozentrum, Department of Biology II (Chair of Anthropology and Human Genetics), Ludwig-Maximilians- University, Grosshadernerstrasse 2, 82152 Martinsried, Germany 2Munich Center for Integrated Protein Sciences (CIPSM), 81377 Munich, Germany Correspondence: [email protected] Chromosome territories (CTs) constitute a major feature of nuclear architecture. In a brief statement, the possible contribution of nuclear architecture studies to the field of epigenom- ics is considered, followed bya historical account of the CT concept and the final compelling experimental evidence of a territorial organization of chromosomes in all eukaryotes studied to date. Present knowledge of nonrandom CT arrangements, of the internal CT archi- tecture, and of structural interactions with other CTs is provided as well as the dynamics of CT arrangements during cell cycle and postmitotic terminal differentiation. The article concludes with a discussion of open questions and new experimental strategies to answer them. mpressive progress has been achieved during for an integrated understanding of the structural Ithe last decade with regard to the functional and functional aspects of epigenetics with nu- implications of DNA methylation, histone mo- clear architecture during the differentiation of difications, and chromatin remodeling events toti- or pluripotent cells to functionally distinct for gene regulation (Fuks 2005; Kouzarides cell types. 2007; Maier et al. 2008; Jiang and Pugh 2009). The territorial organization of chromo- It has, however, also become obvious that somes in interphase (chromosome territories, decoding the chromatin language does not suf- CTs) constitutes a basic feature of nuclear archi- fice to fully understand the ways in which the tecture. This article starts with a brief historical diploid genome contributes to the formation account of the CT concept and the compelling of the different epigenomes present in the vari- experimental evidence in favor of a territorial ous cell types of a multicellular organism. organization of chromosomes in all eukaryotes Different epigenomes and their functional studied to date. A survey of what is presently implications also depend on differences in hig- known about nonrandom arrangements of her-order chromatin organization and nuclear CTs, about changes of such arrangements in architecture at large. Epigenomic research aims cycling cells as a result of internal or external Editors: David Spector and Tom Misteli Additional Perspectives on The Nucleus available at www.cshperspectives.org Copyright # 2010 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a003889 Cite this article as Cold Spring Harb Perspect Biol 2010;2:a003889 1 Downloaded from http://cshperspectives.cshlp.org/ on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press T. Cremer and M. Cremer influences and about the internal architecture 2006a): (I) CTorder is stably maintained during of CTs and their structural interactions with interphase; (II) Chromosome neighborhood each other is provided. The article concludes patterns change from prophase to metaphase; with a discussion of open questions on CT and (III) New chromosome neighborhood arra- organization and new experimental strategies ngements established in the metaphase plate are to answer them. conserved to a considerable extent throughout anaphase and telophase, resulting in rather sym- metrical arrangements of CTs in the two daugh- ter nuclei. Different opinions on the structural ORIGIN OF THE CHROMOSOME organization of CTs were put forward in the TERRITORY CONCEPT early days of the 20th century. Eduard Strasbur- Since the late 19th century, an uncounted ger (1905) published a colored cartoon claiming number of microscopic studies has appeared that CTs are built up from little chromatin on numerous aspects of nuclear structure and clumps (Fig. 1E), whereas Theodor Boveri dis- on the observation of mitotic chromosomes. cussed a sponge-like CT structure built up A territorial organization of interphase chro- from networks of anastomizing chromatin bun- mosomes was first suggested for animal cell dles (Fig. 1F). nuclei by Carl Rabl (Rabl 1885) (Fig. 1A,B), Despite light microscopic evidence in favor but it was Theodor Boveri who introduced of chromosome territories at least in some spe- the term chromosome territory (CT) in his cies and cell types (for review see Stack et al. seminal studies of blastomere stages of the 1977) the weight of electron microscopic evi- horse roundworm Parascaris equorum or Asca- dence established since the 1950s apparently ris megalocephala, as the species was called at argued for an unraveling of chromosomes in his time (Boveri 1909). The worm exists in interphase nuclei into intermingling chromatin two varieties, one with two pairs (Ascaris biva- fibers of 10–30 nm in diameter with no sign lens), the other with one pair of germ line chro- of individual chromosomes. As a consequence, mosomes (Ascaris univalens). Boveri argued the concept of chromosome territories fell into that each chromosome visible in mitosis retains oblivion or was even considered to be ex- its individuality during interphase and occupies perimentally disproved (Wischnitzer 1973). a distinct part of the nuclear space. As can be During the 1970s and 1980s, most researchers seen in his drawings, Boveri was able to distin- seemed content with the assumption that the guish chromosome ends sticking out in protru- nucleus is filled with intermingling chromatin sions of prophase nuclei (Fig. 1C) and used fibers and loops like a dish of spaghetti, an as- these protrusions as markers for the nuclear sumption widely reflected by textbooks of cell position of the asserted CTs in interphase nuclei biology. (Fig. 1D). In fixed two-cell embryos, Boveri noted that their nuclear topography was strik- ingly similar during interphase and prophase, EXPERIMENTAL EVIDENCE FOR when chromosomes became visible as distinct CHROMOSOME TERRITORIES entities. In four cell embryos, however, he typi- cally observed two pairs of nuclei each carry- Stephen M. Stack, David B. Brown, and William ing distinctly different protrusion patterns C. Dewey were among the few researchers in (Fig. 1D). His ingenious speculative talent led the 1970s that still adhered to Boveri’s seemingly him to the following predictions on chromo- outdated concept (Stack et al. 1977; for review, some arrangements in Ascaris nuclei during see Cremer and Cremer 2006b). They squashed the first steps of postzygotic development (for fixed cells from Allium cepa root tips, as well a comprehensive review, see Cremer and Cremer as Chinese hamster cells in acetic acid, and 2 Cite this article as Cold Spring Harb Perspect Biol 2010;2:a003889 Downloaded from http://cshperspectives.cshlp.org/ on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press Chromosome Territories subjected the air-dried cells to salt solutions subset of the mitotic chromosome complement containing NaOH, and finally performed a (Fig. 2D). The labeled parts of mitotic chromo- Giemsa staining. This treatment yielded clumps somes revealed the UV damaged segments of of condensed chromatin arguably reflecting neighboring chromosome territories hit by the interphase chromosomes (Fig. 2A). The authors microbeam during the preceding interphase. concluded that “chromosomes ... remain in Consistent with this result, microirradiation of distinct domains throughout interphase.” Our a small part of the metaphase plate of a living group obtained early evidence for CTs in nuclei cell yielded a mirror-like pattern of distinctly of diploid Chinese hamster cells with the help of labeled domains in the resulting daughter nuclei laser-UV-microirradiation experiments (Zorn (Fig. 2F). These experiments provided the first et al. 1976; Zorn et al. 1979; Cremer et al. compelling, although still indirect, evidence 1982a; Cremer et al. 1982b; for review, see for the existence of chromosome territories. Cremer and Cremer 2006b; Meaburn and Mis- The direct visualization of individual CTs teli 2007). A laser microbeam (l ¼ 257 nm) was made possible by in situ hybridization was used to induce UV-damaged DNA within techniques developed during the mid 1980s. a small part of the nucleus. It was predicted Initial experiments were performed with total that DNA damage inflicted within a small human genomic DNA on cell hybrids that con- volume of the nucleus would yield different tained only one or few human chromosomes results depending on how chromosomes were in a mouse or hamster genome complement arranged. Figure 2B exemplifies the experimen- (Manuelidis 1985; Schardin et al. 1985) (Fig. tal rationale with the example of woolen threads 3A). The achievement of chromosome sorting assembled within a “nuclear” space (Cremer by flow cytometry of fluorescently labeled et al. 1982a). Each thread reflects a chromatin mitotic chromosomes (Cremer et al. 1984a; fiber constituting an individual chromosome. Gray et al. 1987; Fawcett et al. 1994) enabled In case of threads distributed throughout the the generation of chromosome specific painting whole nuclear space (upper panel), the “dam- probes for a large number of species. Subse- age” label would become scattered over many quent amplification of DNA by cloning in bac- threads. If individual threads occupy distinct terial vectors or
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