Spatial organization of active and inactive genes and noncoding DNA within chromosome territories

Mahy, Nicola L.; Perry, Paul; Gilchrist, Susan; Baldock, Richard; Bickmore, Wendy A.

doi:10.1083/jcb.200111071

Cited by 208 publications

(181 citation statements)

References 43 publications

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“…3B). Additionally, as has been reported in other studies (12,16,17), we found that a significant fraction of gene signals overlapped a hole in the DNA paint signal and were scored as IN (Hole) (see Fig. 3 B and C), whereas this was not true for the centromere signals, the majority of which were found inside the territory for both Xa and Xi.…”

Section: Genes Reproducibly Border the Xist Rna Territory Irrespectivsupporting

confidence: 87%

The X chromosome is organized into a gene-rich outer rim and an internal core containing silenced nongenic sequences

Clemson

Hall

Byron

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

192

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We investigated whether genes escape X chromosome inactivation by positioning outside of the territory defined by XIST RNA. Results reveal an unanticipated higher order organization of genes and noncoding sequences. All 15 X-linked genes, regardless of activity, position on the border of the XIST RNA territory, which resides outside of the DAPI-dense Barr body. Although more strictly delineated on the inactive X chromosome (Xi), all genes localized predominantly to the outer rim of the Xi and active X chromosome. This outer rim is decorated only by X chromosome DNA paints and is excluded from both the XIST RNA and dense DAPI staining. The only DNA found well within the Barr body and XIST RNA territory was centromeric and Cot-1 DNA; hence, the core of the X chromosome essentially excludes genes and is composed primarily of noncoding repeat-rich DNA. Moreover, we show that this core of repetitive sequences is expressed throughout the nucleus yet is silenced throughout Xi, providing direct evidence for chromosomewide regulation of ''junk'' DNA transcription. Collective results suggest that the Barr body, long presumed to be the physical manifestation of silenced genes, is in fact composed of a core of silenced noncoding DNA. Instead of acting at a local gene level, XIST RNA appears to interact with and silence core architectural elements to effectively condense and shut down the Xi.Barr body ͉ chromosome territory ͉ nuclear organization ͉ XIST ͉ noncoding RNA X inactivation in mammalian females is a prominent example of the formation of facultative heterochromatin during early development, which prevents the deleterious effects of overexpression of X-linked genes. In interphase, the inactive X chromosome (Xi) is found as a condensed heterochromatic Barr body, usually positioned at the nuclear or nucleolar periphery (1-4). Because many genes have been identified that escape X inactivation, packaging differences of sequences at some level within the Xi is presumed (5, 6). Although it is generally assumed that the Barr body is condensed DNA comprising genes normally expressed on the active X chromosome (Xa), the specific makeup of the Barr body has not been investigated.X inactivation is a multistep process initiated by XIST (7-9). Just after XIST RNA sweeps across the chromosome, a defined pattern of chromatin changes including histone modifications, recruitment of macroH2A, and methylation occurs (for review see refs. 10 and 11). We have shown that XIST RNA remains in the nucleus, functionally associated with the inactive chromatin, forming an interphase territory coincident with Xi (12, 13). We incorporated our results into two models for the higher-level organization of the inactive X chromosome (12). In each alternate view, XIST RNA would induce differences in the packaging of the chromatin to facilitate inactivation. In the first model, all genes, regardless of whether they escape from or are subject to X inactivation, would be interspersed throughout the chromosome territory and would not be cytologically disti...

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Section: Genes Reproducibly Border the Xist Rna Territory Irrespectivsupporting

confidence: 87%

The X chromosome is organized into a gene-rich outer rim and an internal core containing silenced nongenic sequences

Clemson

Hall

Byron

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

192

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“…Furthermore, the position of genes within interphase nuclei is also conserved between species. HSA11p15 and HSA11p13 locate to similar positions with respect to their chromosome territory as their corresponding loci on mouse chromosome (MMU) 7 and MMU2 [23,24]. Finally, the position of genes relative to one another is also conserved; the MLL gene is more peripherally located than AF4 and AF9 in fibroblasts derived from both humans and two species of Muntjac deer [25].…”

Section: Non-random Spatial Positioning Of Chromosomesmentioning

confidence: 99%

“…CD8, on the other hand, becomes more peripherally located upon activation [26]. However, not all genes alter location with changes in activation [24,52,53]. For example, RB1 remains preferentially located towards the nuclear periphery regardless of activity [52].…”

Section: Non-random Spatial Positioning Of Genesmentioning

confidence: 99%

Spatial genome organization in the formation of chromosomal translocations

Meaburn

Misteli

Soutoglou

2007

Seminars in Cancer Biology

178

142

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Chromosomal translocations and genomic instability are universal hallmarks of tumor cells. While the molecular mechanisms leading to the formation of translocations are rapidly being elucidated, a cell biological understanding of how chromosomes undergo translocations in the context of the cell nucleus in vivo is largely lacking. The recent realization that genomes are non-randomly arranged within the nuclear space has profound consequences for mechanisms of chromosome translocations. We review here the emerging principles of spatial genome organization and discuss the implications of non-random spatial genome organization for the genesis and specificity of cancerous chromosomal translocations.

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“…However, internal positions have also been described for expressed genes (Mahy et al 2002b;Stadler et al 2004) and transcription sites (Verschure et al 1999). To investigate the positioning of gene loci relative to their chromosome territory, we compared the distance of each gene locus signal to the territory surface with the distance of territory signal voxels to the territory surface (Fig.…”

Section: Gene Positioning and Expressionmentioning

confidence: 99%

Three-dimensional positioning of genes in mouse cell nuclei

et al. 2008

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To understand the regulation of the genome, it is necessary to understand its three-dimensional organization in the nucleus. We investigated the positioning of eight gene loci on four different chromosomes, including the β-globin gene, in mouse embryonic stem cells and in in vitro differentiated macrophages by fluorescence in situ hybridization on structurally preserved nuclei, confocal microscopy, and 3D quantitative image analysis. We found that gene loci on the same chromosome can significantly differ from each other and from their chromosome territory in their average radial nuclear position. Radial distribution of a given gene locus can change significantly between cell types, excluding the possibility that positioning is determined solely by the DNA sequence. For the set of investigated gene loci, we found no relationship between radial distribution and local gene density, as it was described for human cell nuclei. We did find, however, correlation with other genomic properties such as GC content and certain repetitive elements such as long terminal repeats or long interspersed nuclear elements. Our results suggest that gene density itself is not a driving force in nuclear positioning. Instead, we propose that other genomic properties play a role in determining nuclear chromatin distribution.

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Spatial organization of active and inactive genes and noncoding DNA within chromosome territories

Cited by 208 publications

References 43 publications

The X chromosome is organized into a gene-rich outer rim and an internal core containing silenced nongenic sequences

The X chromosome is organized into a gene-rich outer rim and an internal core containing silenced nongenic sequences

Spatial genome organization in the formation of chromosomal translocations

Three-dimensional positioning of genes in mouse cell nuclei

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