Absence of the XIST gene from late-replicating isodicentric X chromosomes in leukaemia

Rack, Katrina; Chelly, Jamel; Gibbons, Richard J.; Rider, Sue; Benjamin, Dennis R.; Lafrenière, Ronald G.; Oscier, DG; Hendriks, Rudolf W.; Craig, Ian W.; Willard, H.F.

doi:10.1093/hmg/3.7.1053

Cited by 73 publications

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“…The role of XIST in the maintenance of repression has been questioned, however. Previous studies of inactive X chromosomes with XIST deletions indicate that XIST RNA is not necessary to maintain X inactivation (2,3), presumably because other repressive systems, such as promoter methylation, histone deacetylation, and͞or late replication, are maintaining inactivation. Our studies of human-hamster hybrids containing an inactive X chromosome with azacytidine-reactivated genes indicate that XIST expression is not sufficient to prevent reactivation or to reinitiate silencing of these genes (4).…”

mentioning

confidence: 97%

Reactivation of XIST in normal fibroblasts and a somatic cell hybrid: Abnormal localization of XIST RNA in hybrid cells

Hansen

Canfield

Stanek

et al. 1998

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

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The XIST gene, expressed only from the inactive X chromosome, is a critical component of X inactivation. Although apparently unnecessary for maintenance of inactivation, XIST expression is thought to be sufficient for inactivation of genes in cis even when XIST is located abnormally on another chromosome. This repression appears to involve the association of XIST RNA with the chromosome from which it is expressed. Reactivated genes on the inactive X chromosome, however, maintain expression in several somatic cell hybrid lines with stable expression of XIST. We describe here another example of an XIST-expressing humanhamster hybrid that lacks X-linked gene repression in which the human XIST gene present on an active X chromosome was reactivated by treatment with 5-aza-2-deoxycytidine. These data raise the possibility that human XIST RNA does not function properly in human-rodent somatic cell hybrids. As part of our approach to address this question, we reactivated the XIST gene in normal male fibroblasts and then compared their patterns of XIST RNA localization by subcellular fractionation and in situ hybridization with those of hybrid cells. Although XIST RNA is nuclear in all cell types, we found that the in situ signals are much more diffuse in hybrids than in human cells. These data suggest that hybrids lack components needed for XIST localization and, presumably, XIST-mediated gene repression.Stable expression of XIST is required on the inactive X chromosome for the establishment of mammalian X chromosome inactivation (reviewed in ref. 1). The role of XIST in the maintenance of repression has been questioned, however. Previous studies of inactive X chromosomes with XIST deletions indicate that XIST RNA is not necessary to maintain X inactivation (2, 3), presumably because other repressive systems, such as promoter methylation, histone deacetylation, and͞or late replication, are maintaining inactivation. Our studies of human-hamster hybrids containing an inactive X chromosome with azacytidine-reactivated genes indicate that XIST expression is not sufficient to prevent reactivation or to reinitiate silencing of these genes (4). A similar conclusion was reached by other workers studying reactivation of X-linked genes in another cell hybrid system (5).To examine this phenomenon further, we reactivated the silent XIST gene on the human active X chromosome in a human-hamster hybrid and in normal human male fibroblasts. The rationale for reactivation was based on the apparent regulation of XIST expression by 5Ј-CG-3Ј dinucleotide methylation. This region is hypermethylated on the silent, active X allele and is hypomethylated on the expressed, inactive X allele in both human (6, 7) and murine (8-11) somatic tissues. A further indication that 5Ј hypermethylation is important in Xist regulation is that the active X allele is expressed in somatic cells of male mice deficient in DNA methyltransferase (12, 13).Repression by 5Ј-CG-3Ј dinucleotide methylation commonly is found for X-inactivated genes, and reactivat...

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confidence: 97%

Reactivation of XIST in normal fibroblasts and a somatic cell hybrid: Abnormal localization of XIST RNA in hybrid cells

Hansen

Canfield

Stanek

et al. 1998

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

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“…Although considerable attention has been focused on the relative timing and roles of these features during establishment of the Xi heterochromatic state early in development (26), once that epigenetic state is established, they have been widely considered to be redundant (27)(28)(29)(30)(31). One prediction of the epigenetic redundancy model is that the features of facultative heterochromatin should colocalize on the Xi in somatic cells.…”

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confidence: 99%

Multiple spatially distinct types of facultative heterochromatin on the human inactive X chromosome

Chadwick

Willard²

2004

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

215

183

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Heterochromatin is defined classically by condensation throughout the cell cycle, replication in late S phase and gene inactivity. Facultative heterochromatin is of particular interest, because its formation is developmentally regulated as a result of cellular differentiation. The most extensive example of facultative heterochromatin is the mammalian inactive X chromosome (Xi). A variety of histone variants and covalent histone modifications have been implicated in defining the organization of the Xi heterochromatic state, and the features of Xi heterochromatin have been widely interpreted as reflecting a redundant system of gene silencing.However, here we demonstrate that the human Xi is packaged into at least two nonoverlapping heterochromatin types, each characterized by specific Xi features: one defined by the presence of Xi-specific transcript RNA, the histone variant macroH2A, and histone H3 trimethylated at lysine 27 and the other defined by H3 trimethylated at lysine 9, heterochromatin protein 1, and histone H4 trimethylated at lysine 20. Furthermore, regions of the Xi packaged in different heterochromatin types are characterized by different patterns of replication in late S phase. The arrangement of facultative heterochromatin into spatially and temporally distinct domains has implications for both the establishment and maintenance of the Xi and adds a previously unsuspected degree of epigenetic complexity.Barr body ͉ X inactivation ͉ X-inactive-specific transcript

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“…Recent studies, however, demonstrated that the XIST gene and the XIC are not strictly required for the maintenance of X inactivation in somatic hybrid cells (Brown and Willard, 1994) or in leukemic cells with a deleted XIST gene (Rack et al, 1994).…”

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confidence: 99%

Position effect of translocations involving the inactive X chromosome: physical linkage to XIC/XIST does not lead to long-range de novo inactivation in human differentiated cells

Surrallés

Natarajan²

1998

Cytogenet Genome Res

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Given the reported long-range cis-inactivating effect of the XIST gene in early embryonic development and the lack of requirement of X-chromosome-specific elements for propagating the inactive state, there exists the possibility of cis inactivation of autosomal material after de novo translocation to an inactive X chromosome (Xi) in differentiated cells. We have analyzed de novo radiation-induced translocations between the Xi and autosomes to study the maintenance and spreading of X-chromosome inactivation (X inactivation) in relation to the position of the X-inactivation center (XIC)/XIST in differentiated cells. Autosome/Xi translocations were detected by fluorescence in situ hybridization (FISH). The activation status of the chromosomes involved in the translocation was determined by simultaneous immunocytogenetic studies using antibodies against either BrdU incorporated at late S phase or acetylated histone H4. The position of XIC/XIST in the reciprocal products of the translocation was determined by XIST-specific FISH and computer enhancement. In other experiments, the Xq13 region carrying XIC/XIST was localized by computer enhancement of the DAPI banding pattern. Our study in differentiated cells provides a visual demonstration that physical separation from XIC/XIST does not result in reactivation of inactive X-chromosome material and that X inactivation is not spread to the translocated autosomes irrespective of the position of XIC/XIST. This observation suggests that physical linkage to XIC/XIST does not lead to de novo inactivation of autosomal material.

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Absence of the XIST gene from late-replicating isodicentric X chromosomes in leukaemia

Cited by 73 publications

References 0 publications

Reactivation of XIST in normal fibroblasts and a somatic cell hybrid: Abnormal localization of XIST RNA in hybrid cells

Reactivation of XIST in normal fibroblasts and a somatic cell hybrid: Abnormal localization of XIST RNA in hybrid cells

Multiple spatially distinct types of facultative heterochromatin on the human inactive X chromosome

Position effect of translocations involving the inactive X chromosome: physical linkage to XIC/XIST does not lead to long-range de novo inactivation in human differentiated cells

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