Mechanisms of X‐inactivation

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Mechanisms of X‐inactivation

Sarah M Duthie, Medical Research Council Clinical Sciences Centre, London, UK

Published online: April 2001

DOI: 10.1038/npg.els.0001194

Full Article on Wiley Online Library

Abstract
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References

X-inactivation involves the transcriptional silencing of one of the two X-chromosomes in the cells of female mammals. This process is controlled by elements present in the X-inactivation centre (Xic) which is required in cis for X-inactivation to occur.

Keywords: xist; X chromosome inactivation; dosage compensation; chromatin; X inactivation centre

References
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	Johnston CM, Nesterova TB, Formstone EJ et al. (1998) Developmentally regulated Xist promoter switch mediates initiation of X inactivation. Cell 94: 809–817.
	Kay GG, Penny GD, Patel D, Ashworth A, Brockdorff N and Rastan S (1993) Expression of Xist during mouse development suggests a role in the initiation of X chromosome inactivation. Cell 72: 171–182.
	Lee JT, Strauss WM, Dausman JA and Jaenisch R (1996) A 450 kb transgene displays properties of the mammalian X inactivation center. Cell 86: 83–94.
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Further Reading
	Clemson CM, McNeil JA, Willard HF and Lawrence JB (1996) XIST RNA paints the inactive X chromosome at interphase: evidence for a novel RNA involved in nuclear/chromosome structure. Journal of Cell Biology 132: 1–17.
	Cross SH and Bird AP (1995) CpG islands and genes. Current Opinion in Genetics and Development 5: 309–314.
	Heard E, Clerc P and Avner P (1997) X chromosome inactivation in mammals. Annual Review of Genetics 31: 571–610.
	Hendrich BD and Willard HF (1995) Epigenetic regulation of gene expression: the effect of altered chromatin structure from yeast to mammals. Human Molecular Genetics 4: 1765–1777.
	Keohane AM, Lavender JS, O'Neill LP and Turner BM (1998) Histone acetylation and X inactivation. Developmental Genetics 22: 65–73.
	Lyon MF (1992) Some milestones in the history of X-chromosome inactivation. Annual Review of Genetics 26: 16–28.
	Rastan S and Brown SD (1990) The search for the mouse X-chromosome inactivation centre. Genetical Research 56: 99–106.
	book Russell LM (1983) "X-autosome translocations in the mouse: their characterisation and use as tools to investigate gene inactivation and gene action". In: Sandberg AA (ed.) Cytogenetics of the Mammalian X Chromosome. Part A. Basic Mechanisms of X Chromosome Behaviour, pp. 205–250. New York: Alan R Liss.

Article Title:	Mechanisms of X‐inactivation
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	Figure 1. Model for initiation of random X-inactivation. (a) Unstable Xist transcript from P₀ promoter on both alleles. Both X-chromosomes active (Xa). (b) Upon differentiation, a limited amount of blocking factor binds to only one X-chromosome at random – designated Xa. (c) Transcription switches from P₀ to initiation of stable, accumulated Xist RNA from P₁/P₂ on Xi. Xi inactivates. Unstable P₀ transcript still detectable from Xa. (d) Unstable P₀ Xist transcript silenced on Xa.
	Figure 2. The process of X-inactivation. (a) Xist RNA switched off during passage through the germline. (b) Both X-chromosomes active in early cleavage-stage embryo. Stable, accumulated Xist signal associated with paternal X (X^p). (c) By midstage blastocyst, X^p inactive and associated with stable Xist signal in extraembryonic lineages (trophectoderm), maternal X (X^m) active. Unstable Xist RNA visible as punctate dot from both Xist alleles in cells of the inner cell mass (ICM). Both X-chromosomes active. (d) At day 5.5 of development, embryo implants and cells of embryo proper begin to differentiate. Random X-inactivation initiated – most cells now show unstable Xist transcript from Xa and stable, accumulating transcript from Xi. (e) By day 8.5, Xi associated with stable, accumulated Xist transcript, unstable Xist RNA from Xa switched off. Xi inactive and Xa active throughout adult life.
	Figure 3. Model for spreading of X-inactivation. (a) Active X-chromosome (Xa) showing waystation elements present in gene-rich Giemsa-light (G-light) bands. Waystations are absent or inaccessible in condensed, gene-poor G-dark bands. (b) Xist RNA transcribed from the Xic region spreads bidirectionally via waystation elements along the X. Binding causes local changes in chromatin conformation, resulting in condensation of G-light bands. (c) Xist RNA stably associated with condensed, inactive X-chromosome (Xi).

Mechanisms of X‐inactivation

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