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. 2014;11(7):798-807.
doi: 10.4161/rna.29779. Epub 2014 Aug 19.

Coupling of X-chromosome reactivation with the pluripotent stem cell state

Bernhard Payer  1 , Jeannie T Lee  1
Affiliations

Coupling of X-chromosome reactivation with the pluripotent stem cell state

Bernhard Payer et al. RNA Biol. 2014.

Abstract

X-chromosome inactivation (XCI) in female mammals is a dramatic example of epigenetic gene regulation, which entails the silencing of an entire chromosome through a wide range of mechanisms involving noncoding RNAs, chromatin-modifications, and DNA-methylation. While XCI is associated with the differentiated cell state, it is reversed by X-chromosome reactivation (XCR) ex vivo in pluripotent stem cells and in vivo in the early mouse embryo and the germline. Critical in the regulation of XCI vs. XCR is the X-inactivation center, a multigene locus on the X-chromosome harboring several long noncoding RNA genes including, most prominently, Xist and Tsix. These genes, which sit at the top of the XCI hierarchy, are by themselves controlled by pluripotency factors, coupling XCR with the naïve pluripotent stem cell state. In this point-of-view article we review the latest findings regarding this intricate relationship between cell differentiation state and epigenetic control of the X-chromosome. In particular, we discuss the emerging picture of complex multifactorial regulatory mechanisms, ensuring both a fine-tuned and robust X-reactivation process.

Keywords: PRDM14; Tsix; X-chromosome reactivation; Xist; epigenetics; long noncoding RNA; pluripotency; reprogramming; stem cells.

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Figures

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Figure 1. Functional elements of the X-inactivation center (Xic) and their associated pluripotency factor binding hubs. Arrows depict the direction of transcription while the color indicates if elements are (prospective) activators of the X-inactivation master regulator Xist (red) or of its antisense repressor Tsix (green). The ovals represent binding hubs for pluripotency factors, which can either cause repression (blue) or activation (yellow) of the associated target genes.
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Figure 2.Xist regulation mechanisms in pluripotent (left) and differentiated (right) cell states. The mechanisms described in (A) and (B) have been described to occur both during the onset of XCI (red block arrows, left to right), while the mechanism given in (C) during XCR (green block arrow, right to left). (A) In undifferentiated cells, Xist expression is blocked by binding of CTCF to the Xist promotor (left). During differentiation, Jpx RNA becomes expressed and titrates CTCF away from the Xist promoter, allowing Xist to be upregulated (right)., (B) In pluripotent cells, REX1 represses Xist and activates Tsix by binding to their promoters (left)., During differentiation, RNF12 ubiquitinates and targets REX1 for degradation, leading to the activation of Xist expression (right). (C) Before XCR, RNF12 is expressed and Tsix is low, allowing Xist to be expressed (right, see also B). During XCR, PRDM14 binds upstream of Rnf12 where it recruits the PRC2 complex, leading to silencing of Rnf12 by the H3K27me3 mark. This, together with PRDM14-recruitment to Xist intron 1 by Tsix, results in Xist repression (left).
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References

    1. Payer B, Lee JT. X chromosome dosage compensation: how mammals keep the balance. Annu Rev Genet. 2008;42:733–72. doi: 10.1146/annurev.genet.42.110807.091711. - DOI - PubMed
    1. Disteche CM. Dosage compensation of the sex chromosomes. Annu Rev Genet. 2012;46:537–60. doi: 10.1146/annurev-genet-110711-155454. - DOI - PMC - PubMed
    1. Augui S, Nora EP, Heard E. Regulation of X-chromosome inactivation by the X-inactivation centre. Nat Rev Genet. 2011;12:429–42. doi: 10.1038/nrg2987. - DOI - PubMed
    1. Marahrens Y, Panning B, Dausman J, Strauss W, Jaenisch R. Xist-deficient mice are defective in dosage compensation but not spermatogenesis. Genes Dev. 1997;11:156–66. doi: 10.1101/gad.11.2.156. - DOI - PubMed
    1. Yildirim E, Kirby JE, Brown DE, Mercier FE, Sadreyev RI, Scadden DT, Lee JT. Xist RNA is a potent suppressor of hematologic cancer in mice. Cell. 2013;152:727–42. doi: 10.1016/j.cell.2013.01.034. - DOI - PMC - PubMed

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