The 3D Positioning of ANT2 and ANT3 Genes within Female X Chromosome Territories Correlates with Gene Activity

Dietzel, Steffen; Schiebel, Katrin; Little, Graham; Edelmann, Peter; Rappold, Gudrun; Eils, Roland; Cremer, Christoph; Cremer, Thomas

doi:10.1006/excr.1999.4635

Cited by 111 publications

(84 citation statements)

References 65 publications

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“…Although a body of evidence supports that genes are found on the border of chromosome territories (19,20,(49)(50)(51); specific genes have been shown to express from either inside, on the periphery or well outside of the territory (52)(53)(54). Other reports show that sequences (particularly large clusters of genes) move from a more internal to an external location upon transcriptional activation (53,(55)(56)(57). A previous study of two X-linked genes suggested that a gene subject to inactivation was more internal than a gene that escaped X inactivation (57).…”

Section: Discussionmentioning

confidence: 99%

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.

193

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: Discussionmentioning

confidence: 99%

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.

193

192

View full text Add to dashboard Cite

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“…A study of X-linked ANT2 (subject to XCI) and the PAR1 gene ANT3, which escapes inactivation, suggested a differential position between inactive and active alleles. The active alleles were located toward the edge of X chromosome CTs, whereas the inactive ANT2 allele was positioned toward the interior of the Xi CT (28). CT organization has also been linked to the initiation of XCI.…”

Section: Discussionmentioning

confidence: 99%

Chromosome territory reorganization in a human disease with altered DNA methylation

Matarazzo

Boyle

D’Esposito

et al. 2007

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

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Chromosome territory (CT) organization and chromatin condensation have been linked to gene expression. Although individual genes can be transcribed from inside CTs, some regions that have constitutively high expression or are coordinately activated loop out from CTs and decondense. The relationship between epigenetic marks, such as DNA methylation, and higher-order chromatin structures is largely unexplored. DNMT3B mutations in immunodeficiency centromeric instability facial anomalies (ICF) syndrome result in loss of DNA methylation at particular sites, including CpG islands on the inactive X chromosome (Xi). This allows the specific effects of DNA methylation on CTs to be examined. Using fluorescence in situ hybridization, we reveal a differential organization of the human pseudoautosomal region (PAR)2 between the CTs of the X and Y in normal males and the active X (Xa) and the Xi in females. There is also a more condensed chromatin structure on Xi compared with Xa in this region. PAR2 genes are relocalized toward the outside of the Y and Xi CTs in ICF, and on the Xi, we show that this can extend to genes distant from the site of DNA hypomethylation itself. This reorganization is not simply a reflection of the transcriptional activation of the relocalized genes. This report of altered CT organization in a human genetic disease illustrates that DNA hypomethylation at restricted sites in the genome can lead to more extensive changes in nuclear organization away from the original site of epigenetic change. X inactivation ͉ Y chromosomeT o fully understand the orchestration of gene expression, it is necessary to understand how chromatin is spatially organized within the cell nucleus. In particular, the position of a gene with respect to its chromosome territory (CT) and the chromatin condensation of its genomic region have been linked to gene activation and repression (1). Although individual genes can be transcribed from inside of CTs (2), some regions that have constitutively high gene expression (3,4) or are subject to coordinate gene activation during development (5, 6) or differentiation (7) or in response to physiological stimuli (8) locate at the edge or outside of their CT. This level of nuclear reorganization is often accompanied by a visible level of chromatin decondensation (5, 6, 9). The precise function, if any, of repositioning toward the outside of CTs remains unclear (1), but it may allow for genes to access a nuclear environment enriched in the components of the transcription (10) and/or mRNAprocessing machinery (4,11,12) and so enhance the efficiency of transcription.The interplay between this level of higher-order chromatin organization and epigenetic mechanisms that act at primary levels of chromatin structure, such as DNA methylation, is a little-explored area. In plants, changes in the architecture of CTs can be induced by treatment with inhibitors of DNA methylation (13). However, the genome-wide demethylation that follows 5-azacytidine treatment or genetic deficiency in DNA methyltransferase...

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“…Position of genes relative to the harboring territory With regard to the harboring chromosome territory, several studies found a more peripheral or even external positioning for certain expressed genes or gene clusters than for unexpressed controls (Dietzel et al 1999;Volpi et al 2000;Mahy et al 2002a;Williams et al 2002). 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).…”

Section: Gene Positioning and Expressionmentioning

confidence: 99%

“…Studies investigating stably integrated transgenes in cultured hamster and mouse cells described cases where nuclear positioning was indeed expression dependent, with expressed loci more internal than inactive ones (Tumbar and Belmont 2001;Dietzel et al 2004;Chuang et al 2006). Nuclear positioning can be influenced by expression also for endogenous human or mouse gene loci, a fact maybe best illuminated by genes with monoallelic expression, where both genes show a different topology (Dietzel et al 1999;Takizawa et al 2008). Cases of gene repositioning upon transcriptional activation have been documented relative to their chromosome territory (Volpi et al 2000;Williams et al 2002;Chambeyron and Bickmore 2004), relative to centromeric heterochromatin (Brown et al 1997), for movement away from peripheral heterochromatin (Kosak et al 2002;Zink et al 2004;Ragoczy et al 2006;Williams et al 2006) and for other movements towards more central areas (Takizawa et al 2008).…”

Section: Introductionmentioning

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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The 3D Positioning of ANT2 and ANT3 Genes within Female X Chromosome Territories Correlates with Gene Activity

Cited by 111 publications

References 65 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

Chromosome territory reorganization in a human disease with altered DNA methylation

Three-dimensional positioning of genes in mouse cell nuclei

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