The Element(s) at the Nontranscribed <i>Xist</i> Locus of the Active X Chromosome Controls Chromosomal Replication Timing in the Mouse

Diaz-Perez, Silvia; Ouyang, Yan; Perez, Vanessa; Cisneros, Roxanna; Regelson, M.; Marahrens, York

doi:10.1534/genetics.105.043026

Cited by 21 publications

(17 citation statements)

References 39 publications

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“…Based on the evidence that expression of XIST is critical for initiation of X chromosome silencing and early XCI readout (Diaz-Perez et al, 2005; Lucchesi et al, 2005), we initially detected transcripts of XIST . As expected, conventional reverse-transcription (RT)-PCR detected XIST expression in female somatic cells but not in males (Fig.…”

Section: Resultsmentioning

confidence: 99%

X-chromosome inactivation in monkey embryos and pluripotent stem cells

Tachibana

Sparman

et al. 2012

Developmental Biology

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Inactivation of one X chromosome in female mammals (XX) compensates for the reduced dosage of X-linked gene expression in males (XY). However, the inner cell mass (ICM) of mouse preimplantation blastocysts and their in vitro counterparts, pluripotent embryonic stem cells (ESCs), initially maintain two active X chromosomes (XaXa). Random X chromosome inactivation (XCI) takes place in the ICM lineage after implantation or upon differentiation of ESCs, resulting in mosaic tissues composed of two cell types carrying either maternal or paternal active X chromosomes. While the status of XCI in human embryos and ICMs remains unknown, majority of human female ESCs show non-random XCI. We demonstrate here that rhesus monkey ESCs also display monoallelic expression and methylation of X-linked genes in agreement with non-random XCI. However, XIST and other X-linked genes were expressed from both chromosomes in isolated female monkey ICMs indicating that ex vivo pluripotent cells retain XaXa. Intriguingly, the trophectoderm (TE) in preimplantation monkey blastocysts also expressed X-linked genes from both alleles suggesting that, unlike the mouse, primate TE lineage does not support imprinted paternal XCI. Our results provide insights into the species-specific nature of XCI in the primate system and reveal fundamental epigenetic differences between in vitro and ex vivo primate pluripotent cells.

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Section: Resultsmentioning

confidence: 99%

X-chromosome inactivation in monkey embryos and pluripotent stem cells

Tachibana

Sparman

et al. 2012

Developmental Biology

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“…Therefore, disruption of Xist would be predicted to result in earlier replication of the X chromosome. However, recent reports from the Marahrens lab indicate that Cre/loxP-mediated deletion of the murine Xist gene, in adult somatic cells, causes a delay in replication timing of the entire X chromosome [3,4]. In addition, abnormal chromosomal morphologies and secondary rearrangements were observed on the Xist-deleted chromosomes [3].…”

Section: Disruption Of Chromosome “Ginactivation/stability” Centers Rmentioning

confidence: 99%

“…Cre/loxP-mediated disruption of the ASAR6 gene results in extremely late replication, an under-condensed appearance during mitosis, and structural instability of human chromosome 6 [1,2]. In a separate series of experiments, it was found that disruption of the large non-coding RNA gene Xist, results in extremely late replication, abnormal chromatin structure and instability of the X chromosome [3,4]. The Xist gene resides within the X inactivation center, and is known to participate in the silencing of genes during dosage compensation in female cells [5].…”

Section: Introductionmentioning

confidence: 99%

Mammalian chromosomes containcis‐acting elements that control replication timing, mitotic condensation, and stability of entire chromosomes

Thayer

2012

BioEssays

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Recent studies indicate that mammalian chromosomes contain discrete cis-acting loci that control replication timing, mitotic condensation and stability of entire chromosomes. Disruption of the large non-coding RNA gene ASAR6 results in late replication, an under-condensed appearance during mitosis, and structural instability of human chromosome 6. Similarly, disruption of the mouse Xist gene in adult somatic cells results in a late replication and instability phenotype on the X chromosome. ASAR6 shares many characteristics with Xist, including random mono-allelic expression and asynchronous replication timing. Additional ‘chromosome engineering’ studies indicate that certain chromosome rearrangements affecting many different chromosomes display this abnormal replication and instability phenotype. These observations suggest that all mammalian chromosomes contain ‘inactivation/stability centers’ that control proper replication, condensation and stability of individual chromosomes. Therefore, mammalian chromosomes contain four types of cis-acting elements, origins, telomeres centromeres, and ‘inactivation/stability centers’, all functioning to ensure proper replication, condensation, segregation and stability of individual chromosomes.

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“…However, recent studies also showed that conditional deletion of the Xist gene in mouse somatic cells can influence the frequency of reactivation of previously silenced X-linked alleles and the genome stability, suggesting that Xist/XIST expression in differentiated female cells still plays a role in the maintenance of XCI (13,15,16).…”

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confidence: 99%

X-inactivation in female human embryonic stem cells is in a nonrandom pattern and prone to epigenetic alterations

Shen¹,

Matsuno

Fouse³

et al. 2008

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

198

213

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X chromosome inactivation (XCI) is an essential mechanism for dosage compensation of X-linked genes in female cells. We report that subcultures from lines of female human embryonic stem cells (hESCs) exhibit variation (0 -100%) for XCI markers, including XIST RNA expression and enrichment of histone H3 lysine 27 trimethylation (H3K27me3) on the inactive X chromosome (Xi). Surprisingly, regardless of the presence or absence of XCI markers in different cultures, all female hESCs we examined (H7, H9, and HSF6 cells) exhibit a monoallelic expression pattern for a majority of X-linked genes. Our results suggest that these established female hESCs have already completed XCI during the process of derivation and/or propagation, and the XCI pattern of lines we investigated is already not random. Moreover, XIST gene expression in subsets of cultured female hESCs is unstable and subject to stable epigenetic silencing by DNA methylation. In the absence of XIST expression, Ϸ12% of X-linked promoter CpG islands become hypomethylated and a portion of X-linked alleles on the Xi are reactivated. Because alterations in dosage compensation of X-linked genes could impair somatic cell function, we propose that XCI status should be routinely checked in subcultures of female hESCs, with cultures displaying XCI markers better suited for use in regenerative medicine.culture variation ͉ DNA methylation ͉ gene regulation H uman embryonic stem cells (hESCs) are regarded as one of the most promising stem cells for regenerative medicine because of their unusual capacity of self-renewal and pluripotency (1). However, given the variations in the derivation and propagation of hESCs in different laboratories, it is imperative to establish a common set of criteria for the quality control of hESCs. Efforts have been devoted to characterizing whether established lines of hESCs carry inherent differences in gene expression and epigenetic modifications such as DNA methylation (2). Although different lines of hESCs can exhibit a common set of stem cell markers, differences in gene expression are observed including allelic expression of several imprinted genes and XIST, a crucial gene for X-inactivation (2). Several studies also demonstrated that in vitro cultures or differentiation of hESCs can contribute to changes in CpG methylation patterns and genome stability in different lines of hESCs (2-4). Thus, routine and thorough characterization of genetic and epigenetic stability in hESCs is a necessary step to ensure the quality of hESCs for regenerative medicine.X chromosome inactivation (XCI) is required for dosage compensation of X-linked genes in female cells (5). So far, only a few studies have examined XCI in female hESCs and conflicting data exist regarding the nature of XCI. It has been reported that Ϸ50% of all established female hESC lines exhibit XCI markers such as XIST expression and/or punctate histone H3 lysine 27 trimethylation (H3K27me3) staining on the inactive X chromosome (Xi), whereas other lines do not (2, 6-9). Moreover, discrepan...

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The Element(s) at the Nontranscribed Xist Locus of the Active X Chromosome Controls Chromosomal Replication Timing in the Mouse

Cited by 21 publications

References 39 publications

X-chromosome inactivation in monkey embryos and pluripotent stem cells

X-chromosome inactivation in monkey embryos and pluripotent stem cells

Mammalian chromosomes containcis‐acting elements that control replication timing, mitotic condensation, and stability of entire chromosomes

X-inactivation in female human embryonic stem cells is in a nonrandom pattern and prone to epigenetic alterations

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