Localization of the X inactivation centre on the human X chromosome in Xq13

Brown, Carolyn J.; Lafrenière, Ronald G.; Powers, Vicki E. C.; Sebastio, Gianfranco; Ballabio, Andrea; Pettigrew, Anjana L.; Ledbetter, David H.; Levy, Elaine R.; Craig, Ian W.; Willard, Huntington F.

doi:10.1038/349082a0

Cited by 357 publications

(190 citation statements)

References 26 publications

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“…In the last few years significant insight into the pairing of the two X chromosomes was obtained. Critical for X inactivation is the Xic (X inactivation center) region (Brown et al 1991;Lee 2005). In two elegant studies, the groups of Lee and Heard (Bacher et al 2006;Xu et al 2006) used FISH in mouse female embryonic stem (ES) cells to demonstrate that during the onset of X inactivation, the X chromosomes move from the nuclear periphery, where they have random positions relative to each other, and come into close proximity with their Xic regions juxtaposed.…”

Section: Homologous Interchromosomal Interactionsmentioning

confidence: 99%

Dynamics and interplay of nuclear architecture, genome organization, and gene expression

Schneider¹,

Grosschedl²

2007

Genes Dev.

369

313

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The organization of the genome in the nucleus of a eukaryotic cell is fairly complex and dynamic. Various features of the nuclear architecture, including compartmentalization of molecular machines and the spatial arrangement of genomic sequences, help to carry out and regulate nuclear processes, such as DNA replication, DNA repair, gene transcription, RNA processing, and mRNA transport. Compartmentalized multiprotein complexes undergo extensive modifications or exchange of protein subunits, allowing for an exquisite dynamics of structural components and functional processes of the nucleus. The architecture of the interphase nucleus is linked to the spatial arrangement of genes and gene clusters, the structure of chromatin, and the accessibility of regulatory DNA elements. In this review, we discuss recent studies that have provided exciting insight into the interplay between nuclear architecture, genome organization, and gene expression.

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Section: Homologous Interchromosomal Interactionsmentioning

confidence: 99%

Dynamics and interplay of nuclear architecture, genome organization, and gene expression

Schneider¹,

Grosschedl²

2007

Genes Dev.

369

313

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“…This has been attributed to failure of dosage compensation, by X chromosome inactivation, for the genes on the ring chromosome. 1 ± 3 A region of the proximal long arm of the X chromosome is required in cis for inactivation of the chromosome, 4,5 and contains the XIST gene, which is expressed exclusively from the inactive X chromosome 6 and is necessary for X inactivation in mice (reviewed in Avner and Heard 7 ). Smaller ring chromosomes may lack the XIST locus, rendering them functionally disomic for the genes present on the ring.…”

Section: Introductionmentioning

confidence: 99%

Lack of expression of XIST from a small ring X chromosome containing the XIST locus in a girl with short stature, facial dysmorphism and developmental delay

et al. 2002

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A 46,X,r(X) karyotype was found in a three and a half year old girl with short stature, facial dysmorphism and developmental delay. The clinical findings were consistent with the phenotype described in a limited number of patients with small ring X chromosomes lacking the XIST locus, a critical player in the process of X chromosome inactivation. Surprisingly, in our patient, fluorescent in situ hybridisation demonstrated that the XIST locus was present on the ring X. However, expression studies showed that there was no XIST transcript in peripheral blood cells, suggesting that the ring X had not been inactivated. This was confirmed by the demonstration that both of the patient's alleles for the androgen receptor gene were unmethylated, and that both of the patient's ZXDA alleles were expressed. The active nature of the ring X would presumably result in overexpression of genes that may account for the developmental delay observed for the patient. Using polymorphic markers along the X chromosome, the ring X was determined to be of paternal origin with one breakpoint in the long arm between DXS8037 and XIST and one in the short arm in Xp11.2 between DXS1126 and DXS991. To attempt to determine why the XIST gene failed to be expressed, the promoter region was sequenced and found to have a base change at the same location as a variant previously associated with nonrandom X chromosome inactivation. This mutation was not seen in over one hundred normal X chromosomes examined; however, it was observed in the paternal grandmother who did not show substantial skewing of X chromosome inactivation.

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“…X inactivation is a multistep process initiated by XIST (7)(8)(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.…”

mentioning

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.

194

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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Localization of the X inactivation centre on the human X chromosome in Xq13

Cited by 357 publications

References 26 publications

Dynamics and interplay of nuclear architecture, genome organization, and gene expression

Dynamics and interplay of nuclear architecture, genome organization, and gene expression

Lack of expression of XIST from a small ring X chromosome containing the XIST locus in a girl with short stature, facial dysmorphism and developmental delay

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

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