Failure of extra-embryonic progenitor maintenance in the absence of dosage compensation

Mugford, Joshua W.; Yee, Della; Magnuson, Terry

doi:10.1242/dev.076497

Cited by 28 publications

(20 citation statements)

References 38 publications

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“…Lack of imprinted XCI is supported by studies in rabbit parthenogenotes, and in human and horse placenta 34,50 . By contrast, early X silencing seems to be essential in mice to quickly ensure correct dosage given fast embryonic development 51 . Comparisons between mice and humans with sex chromosome aneuploidy also highlight the importance of early paternal X silencing in mice: only XmXpY (where Xm denotes the maternal X chromosome and Xp the paternal X chromosome), but not XmXmY, karyotypes survive in rodents 52 , whereas equal percentages of these karyotypes are observed in humans 53 .…”

Section: Variable XCI Initiation and Mosaic X Expressionmentioning

confidence: 96%

X chromosome regulation: diverse patterns in development, tissues and disease

et al. 2014

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Genes on the mammalian X chromosome are present in one copy in males and two copies in females. The complex mechanisms that regulate the X chromosome lead to evolutionary and physiological variability in gene expression between species, the sexes, individuals, developmental stages, tissues and cell types. In early development, delayed and incomplete X chromosome inactivation (XCI) in some species causes variability in gene expression. Additional diversity stems from escape from XCI and from mosaicism or XCI skewing in females. This causes sex-specific differences that manifest as differential gene expression and associated phenotypes. Furthermore, the complexity and diversity of X dosage regulation affect the severity of diseases caused by X-linked mutations.

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Section: Variable XCI Initiation and Mosaic X Expressionmentioning

confidence: 96%

X chromosome regulation: diverse patterns in development, tissues and disease

et al. 2014

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“…A recent study (Mugford et al, 2012) reported that the poor trophectoderm development in E6.5 embryos with a paternal Xist deletion is due to premature differentiation and depletion of Cdx2-positive trophoblast progenitors, rather than to TGC growth and differentiation defects. However, another study (Hoki et al, 2011) showed that the development of secondary TGCs is impaired in the context of an Xist hypomorph that survives to E12.5.…”

Section: Research Articlementioning

confidence: 99%

Unusual chromatin status and organization of the inactive X chromosome in murine trophoblast giant cells

et al. 2013

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SUMMARYMammalian X-chromosome inactivation (XCI) enables dosage compensation between XX females and XY males. It is an essential process and its absence in XX individuals results in early lethality due primarily to extra-embryonic defects. This sensitivity to X-linked gene dosage in extra-embryonic tissues is difficult to reconcile with the reported tendency of escape from XCI in these tissues. The precise transcriptional status of the inactive X chromosome in different lineages has mainly been examined using transgenes or in in vitro differentiated stem cells and the degree to which endogenous X-linked genes are silenced in embryonic and extra-embryonic lineages during early postimplantation stages is unclear. Here we investigate the precise temporal and lineage-specific X-inactivation status of several genes in postimplantation mouse embryos. We find stable gene silencing in most lineages, with significant levels of escape from XCI mainly in one extra-embryonic cell type: trophoblast giant cells (TGCs). To investigate the basis of this epigenetic instability, we examined the chromatin structure and organization of the inactive X chromosome in TGCs obtained from ectoplacental cone explants. We find that the Xist RNA-coated X chromosome has a highly unusual chromatin content in TGCs, presenting both heterochromatic marks such as H3K27me3 and euchromatic marks such as histone H4 acetylation and H3K4 methylation. Strikingly, Xist RNA does not form an overt silent nuclear compartment or Cot1 hole in these cells. This unusual combination of silent and active features is likely to reflect, and might underlie, the partial activity of the X chromosome in TGCs.

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“…XCI first takes place with a bias to silencing the paternal X chromosome (Xp) during preimplantation stages (imprinted XCI) and is maintained in the trophectoderm and primitive endoderm lineages (Takagi and Sasaki, 1975). The absence of dosage compensation causes an arrest in proliferation of the progenitor cells of the trophoblast and results in the failure of placental differentiation (Mugford et al, 2012;Roberts et al, 2004). It is likely that the defects in the extraembryonic tissues lead to deterioration in the subsequent development of embryonic tissues (Takagi and Abe, 1990).…”

Section: Introductionmentioning

confidence: 99%

Defects in dosage compensation impact global gene regulation in the mouse trophoblast

et al. 2017

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Xist RNA, which is responsible for X inactivation, is a key epigenetic player in the embryogenesis of female mammals. Of the several repeats conserved in Xist RNA, the A-repeat has been shown to be essential for its silencing function in differentiating embryonic stem cells. Here, we introduced a new Xist allele into mouse that produces mutated Xist RNA lacking the A-repeat (Xist CAGΔ5′ ). Xist CAGΔ5′ RNA expressed in the embryo coated the X chromosome but failed to silence it. Although imprinted X inactivation was substantially compromised upon paternal transmission, allele-specific RNA-seq in the trophoblast revealed that Xist CAGΔ5′ RNA still retained some silencing ability. Furthermore, the failure of imprinted X inactivation had more significant impacts than expected on genome-wide gene expression. It is likely that dosage compensation is required not only for equalizing X-linked gene expression between the sexes but also for proper global gene regulation in differentiated female somatic cells.

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Failure of extra-embryonic progenitor maintenance in the absence of dosage compensation

Cited by 28 publications

References 38 publications

X chromosome regulation: diverse patterns in development, tissues and disease

X chromosome regulation: diverse patterns in development, tissues and disease

Unusual chromatin status and organization of the inactive X chromosome in murine trophoblast giant cells

Defects in dosage compensation impact global gene regulation in the mouse trophoblast

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