Mechanisms of X‐inactivation


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

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 P0Xist 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 (Xp). (c) By midstage blastocyst, Xp inactive and associated with stable Xist signal in extraembryonic lineages (trophectoderm), maternal X (Xm) 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).



Brown CJ, Ballabio A, Rupert JL et al. (1991) A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome. Nature 349: 38–44.

Clerc P and Avner P (1998) Role of the region 3′ to Xist exon 6 in the counting process of X‐chromosome inactivation. Nature Genetics 19: 249–253.

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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.

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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.

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.

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Duthie, Sarah M(Apr 2001) Mechanisms of X‐inactivation. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1038/npg.els.0001194]