Xist and the order of silencing - PubMed (original) (raw)
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Xist and the order of silencing
Karen Ng et al. EMBO Rep. 2007 Jan.
Abstract
X inactivation is the mechanism by which mammals adjust the genetic imbalance that arises from the different numbers of gene-rich X-chromosomes between the sexes. The dosage difference between XX females and XY males is functionally equalized by silencing one of the two X chromosomes in females. This dosage-compensation mechanism seems to have arisen concurrently with early mammalian evolution and is based on the long functional Xist RNA, which is unique to placental mammals. It is likely that previously existing mechanisms for other cellular functions have been recruited and adapted for the evolution of X inactivation. Here, we critically review our understanding of dosage compensation in placental mammals and place these findings in the context of other cellular processes that intersect with mammalian dosage compensation.
Figures
Figure 1
Xist RNA encompasses the X from which it is transcribed. RNA-fluorescence in situ hybridization detecting Xist RNA (red) localized on the inactive X in a preparation of condensed chromosomes from differentiated mouse cells. DNA is counterstained (blue).
Figure 2
The X-inactivation centre regulates Xist expression to ensure that one X chromosome remains active. (A) Map of the regulatory elements implicated in counting and choice in the mouse Xic locus. The Xist gene, the antisense Tsix RNA, Xite, CCCTC-binding factor (CTCF)-binding sites at DXPas34 and the region implicated for Xic pairing are indicated. (B) Proposed scheme of counting and choice that involves pairing of the Xic loci at the initiation of X-inactivation. Homologous X-chromosomes within one nucleus are shown and the Xic is highlighted in red. Pairing of the Xic loci could activate Xist transcription on one chromosome, therefore enforcing the commitment to become silenced, while the other chromosome remains active. Xa, active X; Xi, inactive X; Xic, X-inactivation centre.
Figure 3
Models for Xist spreading along the chromosome in cis. Xist RNA (red) and protein factors postulated to bind Xist (orange) are shown. (A) Xist spreading along the chromosome by means of ‘way stations' or ‘boosters'. (B) Xist spreading based on a cooperative binding mechanism. Xist spreads in cis from its transcription site, where the high RNA concentration is predicted to nucleate chromatin attachment. (C) Schematic representation of the Xi territory with Xist spreading inward from the Xic to the centre of the chromosome territory. LINEs, long interspersed elements; Xic, X-inactivation centre.
Figure 4
Establishing a stable inactive X for the maintenance of X inactivation. (A) Xist triggers reversible chromosomal silencing in the initiation phase of X-inactivation. In differentiated cells, the silent state no longer depends on Xist and is irreversible. (B) A model of Polycomb group (PcG) protein action to maintain repressed states of developmental control genes. A repressor (red) acts transiently and shuts down gene expression. PcG proteins bind and maintain the repression independent of the repressor. (C) A model depicting the establishment of a chromosomal memory by PcG complexes in the initiation phase of X inactivation. The memory could either be a factor, a chromatin modification or a structural change on the chromosome. Xi, inactive X.
Martin Leeb, Anton Wutz, Karen Ng & Dieter Pullirsch
References
- Bacher CP, Guggiari M, Brors B, Augui S, Clerc P, Avner P, Eils R, Heard E (2006) Transient colocalization of X-inactivation centres accompanies the initiation of X inactivation. Nat Cell Biol 8: 293–299 - PubMed
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- Chao W, Huynh KD, Spencer RJ, Davidow LS, Lee JT (2002) CTCF, a candidate trans-acting factor for X-inactivation choice. Science 295: 345–347 - PubMed
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