Abstract
In many sexually dimorphic species, a mechanism is required to ensure equivalent levels of gene expression from the sex chromosomes. In mammals, such dosage compensation is achieved by X-chromosome inactivation, a process that presents a unique medley of biological puzzles: how to silence one but not the other X chromosome in the same nucleus; how to count the number of X's and keep only one active; how to choose which X chromosome is inactivated; and how to establish this silent state rapidly and efficiently during early development. The key to most of these puzzles lies in a unique locus, the X-inactivation centre and a remarkable RNA — Xist — that it encodes.
Key Points
-
In mammals, dosage compensation involves silencing one of the two X chromosomes early during female development — a process known as X inactivation.
-
X inactivation is controlled by a complex genetic locus called the X-chromosome-inactivation centre (Xic ).
-
A key gene within Xic is Xist, which encodes a non-coding nuclear RNA. Xist RNA is essential for X inactivation and coats the X early during the inactivation process
-
Antisense transcription across Xist (leading to production of the Tsix transcript) is thought to be important in the regulation of Xist expression and in mechanisms of choice in X inactivation.
-
Several events occur after Xist expression and are thought to stabilize the inactivity of the chromosome. Comparisons with Drosophila indicate that Xist might help to recruit protein complexes to the inactiving chromosome.
-
Further (and later) features of the inactive X include hypermethylation of DNA, histone deacetylation, chromatin condensation, late replication and association with the variant histone macroH2A.
-
X inactivation is imprinted in extra-embryonic tissues of eutherian mammals. The paternal chromosome is preferentially inactivated and this might reflect the special state of the genome after passage through the paternal genome. Maternal imprinting of the X chromosome also contributes to preferential inactivation.
-
There is some evidence that repeats such as LINE-1 elements might influence the spreading of inactivity from the Xic.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Heard, E., Clerc, P. & Avner, P. X-chromosome inactivation in mammals. Annu. Rev. Genet. 31, 571–610 (1997).A thorough review of the older X–inactivation literature.
Courtier, B., Heard, E. & Avner, P. Xce haplotypes show modified methylation in a region of the active X chromosome lying 3′ to Xist. Proc. Natl Acad. Sci USA 92, 3531–3535 (1995).
Lee, J. T., Davidow, L. S. & Warshawsky, D. TsiX, a gene antisense to Xist at the X-inactivation centre. Nature Genet. 21, 400–404 (1999).This paper first described the presence of antisense transcripts overlapping that of the Xist gene.
Keohane, A. M., O'Neill,L. P., Belyaev, N. D., Lavender, J. S. & Turner, B. M. X-inactivation and H4 acetylation in embryonic stem cells. Dev. Biol. 180, 618–630 (1996).
Mermoud, J. E., Costanzi, C., Pehrson, J. R. & Brockdorff, N. Histone MacroH2A relocates to the inactive X chromosome after initiation and propagation of X-inactivation. J. Cell Biol. 147, 1399–1408 (1999).
Sado, T. et al. X inactivation in the mouse embryo deficient for Dnmt1: distinct effect of hypomethylation on imprinted and randon X inactivation. Dev. Biol. 225, 294–303 (2000).
Lyon, M. F. Some milestones in the history of X-chromosome inactivation. Annu. Rev. Genet. 26, 15–27 ( 1992).
Panning, B., Dausman, J. & Jaenisch, R. X chromosome inactivation is mediated by Xist RNA stabilisation . Cell 90, 907–916 (1997).
Sheardown, S. A. et al. Stabilisation of Xist RNA mediates initiation of X chromosome inactivation. Cell 91, 99– 107 (1997).
Johnston, C. M. et al. Developmentally regulated Xist promoter switch mediates initiation of X inactivation. Cell 94, 809– 817 (1998).
Warshawsky, D., Stavropoulos, N. & Lee, J. T. Further examination of the Xist promoter-switch hypothesis in X inactivation: evidence against the existence and function of a P0 promoter. Proc. Natl Acad. Sci. USA 96, 14424–14429 (1999).
Romer, J. T. & Ashworth, A. The upstream region of the mouse xist gene contains two ribosomal protein pseudogenes. Mamm. Genome. 11, 461–463 ( 2000).
O'Neill, L. P. et al. A developmental switch in H4 acetylation upstream of Xist plays a role in X chromosome inactivation. EMBO J. 18, 2897–2907 (1999).
Wutz, A. & Jaenisch, R. A shift from reversible to irreversible X inactivation is triggered during ES cell differentiation. Mol. Cell 5, 695–705 ( 2000).An important paper describing studies with an inducible Xist cDNA transgene in ES cells, providing definitive evidence that Xist RNA is sufficient for inactivation in cis . In undifferentiated ES cells, Xist RNA coating leads to gene repression but not full inactivation. Upon differentiation, Xist RNA is initially required for X inactivation during a limited window of time, but is subsequently dispensable.
Heard, E. et al. Human XIST yeast artificial chromosome transgenes show partial X inactivation center function in mouse embryonic stem cells. Proc. Natl Acad. Sci. USA 96, 6841– 6846 (1999).
Penny, G. D., Kay, G. F., Sheardown, S. A., Rastan, S. & Brockdorff, N. Requirement for Xist in X chromosome inactivation. Nature 379, 131 –137 (1996).
Marahrens, Y., Panning, B., Dausman, J., Strauss, W. & Jaenisch, R. Xist-deficient mice are defective in dosage compensation but not spermatogenesis. Genes Dev. 11, 156–166 (1997).
Heard, E. et al. Transgenic mice carrying an Xist-containing YAC. Hum. Mol Genet. 5, 441–450 (1996).
Matsuura, S., Episkopou, V., Hamvas, R. & Brown, S. D. M. Xist expression from an Xist transgene carried on the mouse Y chromosome . Hum. Mol. Genet. 5, 451– 459 (1996)
Lee, J. T., Strauss, W. M., Dausman, J. A. & Jaenisch, R. A 450 kb transgene displays properties of the mammalian X-inactivation center . Cell 86, 83–94 (1996).
Heard, E., Mongelard, F., Arnaud, D. & Avner, P. Xist Yeast artificial chromosome transgenes functions as X-inactivation centers only in multicopy arrays and not as single copies. Mol. Cell. Biol. 19, 3156–3166 (1999).A transgenic analysis suggesting that additional, as-yet-undefined functions, other than those covered by the Xist gene and its immediate flanking regions, are necessary for counting and choice to occur.
Stuckenholz, C. Kageyama, Y. & Kuroda, M. I. Guilt by association: non-coding RNAs, chromosome-specific proteins and dosage compensation in Drosophila. Trends Genet. 15, 454–458 ( 1999).
Akhtar, A., Zink, D. & Becker, P. B. A chromodomain-RNA interaction targets MOF to the Drosophila X chromosome. Nature 407, 405–409 (2000).Interesting data on the role of non-coding RNAs in anchoring members of the dosage compensation complex in Drosophila (including the MOF protein, which has acetyltransferase activity) to the male X chromosome.
Gilbert, S. L., Pehrson, J. R. & Sharp, P. A. XIST RNA associates with specific regions of the inactive X chromatin. J. Biol. Chem. 275, 36491–36494 (2000).
Jeppesen, P. & Turner, B. M. The inactive X chromosome in female mammals is distinguished by a lack of histone H4 acetylation, a cytogenetic marker for gene expression. Cell 74, 281 –289 (1993).
Boggs, B. A., Connors, B., Sobel, R. E., Chinault, A. C. & Allis, C. D. Reduced levels of histone H3 acetylation on the inactive X chromosome in human females. Chromosoma 105, 303–309 (1996).
Gilbert, S. L. & Sharp, P. A Promoter-specific hypoacetylation of X-inactivated genes. Proc. Natl Acad. Sci USA 96, 13825–13830 ( 1999).
Costanzi, C. & Pehrson, J. R. Histone macroH2A1 is concentrated in the inactive X chromosome of female mammals. Nature 393, 599–601 (1998).
Rasmussen, T. P. et al. Dynamic relocalization of histone macroH2A1 from centrosomes to inactive X chromosomes during X inactivation. J. Cell Biol. 150, 1189–1198 ( 2000).
Perche, P. -Y. Concentrations of histone MacroH2A in the Barr body are correlated with higher nucleosome density. Curr. Biol. 10, 1581 –1534 (2000).
Csankovski, G., Panning, B., Bates, B., Pehrson, J. R. & Jaenisch, R. Deletion of Xist disrupts histone macroH2A localization but not maintenance of X inactivation. Nature Genet. 22, 323–324 (1999). Shows that Xist RNA coating is necessary for macroH2A accumulation on the inactive X in somatic cells, but neither Xist RNA nor macroH2A are necessary for the maintenance of the inactive state.
Costanzi, C., Stein, P., Worrad, D. M., Schultz, R. M. & Pehrson, J. R. Histone macroH2A is concentrated in the inactive X chromosome of female preimplantation mouse embryos. Development 127, 2283–2289 ( 2000).This paper describes the unexpectedly early association of macroH2A with the X chromosome during imprinted X inactivation, which contrasts with its much later association during random X inactivation.
Clerc, P. & Avner, P. Role of the region 3′ to Xist exon 6 in the counting process of X chromosome inactivation. Nature Genet. 19, 249–253 (1998).Provides the first molecular evidence for counting element(s) that are localized in a region lying 3′ to the mouse Xist gene.
Debrand, E., Chureau, E., Arnaud, D., Avner, P. & Heard, E. Functional analysis of the DXPas34 locus: A 3′ regulator of Xist expression. Mol. Cell. Biol. 19, 8513–8525 (1999).
Lu, N. & Lee, J. T. Targeted mutagenesis of Tsix leads to nonrandom X inactivation. Cell 99, 47 –57 (1999).
Gribnau, J., Diderich, K., Pruzina, S., Calzolari, R. & Fraser, P. Intergenic transcription and developmental remodeling of chromatin subdomains in the human β-globin locus. Mol. Cell 5, 377–386 ( 2000).
Travers, A. Chromatin modification by DNA tracking. Proc. Natl Acad. Sci USA 96, 13634–13637 ( 1999).
Simmler, M. C., Cattanach, B. M., Rasberry, C., Rouguelle, C. & Avner, P. Mapping the murine Xce locus with (CA)n repeats. Mamm. Genome 4, 523– 530 (1993)
Plenge, R. M. et al. A promoter mutation in the XIST gene in two unrelated families with skewed X-chromosome inactivation. Nature Genet. 14, 353–356 (1997)
Marahrens, Y., Loring, J. & Jaenisch, R. Role of the Xist gene in X chromosome choosing, Cell 92, 657–664(1998).
Graves, J. A. Mammals that break the rules: genetics of marsupials and monotremes. Annu. Rev. Genet. 30, 233–260 (1996).
Richler, C., Dhara, S. K. & Wahrman, J. Histone macroH2A 1. 2 is concentrated in the XY compartment of mammalian male meiotic nuclei. Cytogenet. Cell. Genet. 89, 118–120 (2000).
Hoyer-Fender, S., Costanzi, C. & Pehrson, J. R. Histone macroH2A1.2 is concentrated in the XY-body by the early pachytene stage of spermatogenesis. Exp. Cell Res. 258, 254–260 ( 2000).
Mayer, W., Niveleau, A., Walter, J., Fundele, R. & Haaf, T. Demethylation of the zygotic paternal genome. Nature 403, 501–502 ( 2000).
Ferreira, J. & Carmo-Fonseca, M. Genome replication in early mouse embryos follows a defined temporal and spatial order. J. Cell Sci. 110, 889–897 ( 1997).
Mayer, W., Smith, A., Fundele, R. & Haaf, T. Spatial separation of parental genomes in preimplantation mouse embryos. J. Cell Biol. 148, 629–634 ( 2000).
Eggan, K. et al. Non-random and random X chromosome inactivation in cloned embryos . Science 290, 1578–1581 (2000).The first use of somatic nuclear transfer to explore facets of the biology of X inactivation.
Okamoto, I., Tan, S. S. & Takagi, N. X chromosome inactivation in XX androgenetic mouse embryos surviving implantation. Development 127, 4137–4145 (2000).
Goto,Y. & Takagi, N. Maternally inherited X chromosome is not inactivated in mouse blastocysts due to parental imprinting. Chromosome Res. 7, 101–109 (1999).
Tada, T. et al. Imprint switching for non random X-chromosome inactivation during mouse oocyte growth. Development 127, 3101 –3103 (2000).
McDonald, L. E., Paterson, C. A. & Kay, G. F. Bisulfite genomic sequencing-derived methylation profile of the Xist gene throughout early mouse development. Genomics 54, 379–386 ( 1998).
Lee, J. T. Disruption of imprinted X inactivation by parent-of-origin effects at TsiX . Cell 103, 17–27 (2000).
Prissette, M., El-Maarri, O., Arnaud, D., Walter, J. & Avner, P. Methylation profiles of the DXPas34 locus during the onset of X–inactivation. Hum. Mol. Genet. (in the press).
White, W. M., Willard, H. F., Van Dyke, D. L. & Wolff, D. J. The spreading of X inactivation into autosomal material of an X;autosome translocation: evidence for a difference between autosomal and X-chromosomal DNA. Am. J. Hum. Genet. 63, 20–28 (1998)
Duthie, S. M. et al. Xist RNA exhibits a banded localization on the inactive X chromosome and is excluded from autosomal material in cis. Hum. Mol. Genet. 8, 195–204 (1999).
Riggs, A. D. Marsupials and mechanisms of X chromosome inactivation. Aust. J. Zool. 37, 419–441 ( 1990)
Bailey, J. A., Carrel, L., Chakravarti, A. & Eichler, E. E. Molecular evidence for a relationship between LINE-1 elements and X chromosome inactivation: the Lyon repeat hypothesis. Proc. Natl Acad. Sci. USA 97, 6634–6639 ( 2000).
Carrel, L., Cottle, A. A., Goglin, K. C. & Willard, H. F. A first generation X-inactivation profile of the human X chromosome. Proc. Natl Acad. Sci. USA 96, 14440– 14444 (1999).
Watanabe, Y., Tenzen, T., Nagasaka, Y., Inoko, H. & Ikemura, T. Replication timing of the human X-inactivation center (XIC) region: correlation with chromosome bands. Gene 252, 163–172 (2000).
Keohane, A. M., Barlow, A. L., Waters, J., Bourn, D. & Turner, B. M. H4 acetylation, XIST RNA and replication timing are coincident and define X; autosome boundaries in tow abnormal X chromosomes. Hum. Mol. Genet. 8, 377– 383 (1999).
Disteche, C. M. Escapees on the X chromosome. Proc. Natl Acad. Sci. USA 96, 14180–14182 (1999).
DeBerardinis, R. J., Goodier, J. L., Ostertag, E. M. & Kazazian, H. H. Jr Rapid amplification of a retrotransposon subfamily is evolving the mouse genome. Nature Genet. 20, 288–290 (1998).
Lingenfelter, P. A. et al. Escape from X inactivation is preceded by silencing during development. Nature Genet. 18, 212– 213 (1999).
Sanford, J. P., Clark, H. J., Chapman, V. M. & Rossant, J. Differences in DNA methylation during oogenesis and spermatogenesis and their persistence during early embryogenesis in the mouse. Genes Dev. 1, 1039–1046 ( 1987)
Xu, G. L. et al. Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature 402 , 187–190 (1999).
Amir, R. E. et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nature Genet. 23, 185–188 (1999).
Simmler, M. C. et al. Localisation and expression analysis of a novel conserved brain expressed sequence, Brx/BRX, lying within the Xic/XIC candidate region . Mamm. Genome 8, 760–766 (1997).
Cunningham, D. B., Segretain, D., Arnaud, D., Rogner, U. C. & Avner, P. The Mouse Tsx gene is expressed in Sertoli cells of the adult testis and transiently in premeiotic germ cells during puberty. Dev. Biol. 204, 345– 360 (1998).
Horn, J. H. & Ashworth, A. A member of the caudal family of homeobox genes maps to the X-inactivation centre region of the mouse and human X chromosomes. Hum. Mol. Genet. 4, 1041– 1047 (1995).
Rougeulle, C. & Avner, P. Identification of an S19 pseudogene lying close to the Xist sequence in the mouse. Mamm. Genome 7, 606–607 (1996)
Lyon, M. F. X-chromosome inactivation: a repeat hypothesis. Cytogenet. Cell Genet. 80, 133–137 ( 1998).
Author information
Authors and Affiliations
Supplementary information
Related links
Related links
DATABASE LINKS
ENCYCLOPEDIA OF LIFE SCIENCES
Glossary
- CHROMODOMAIN
-
A highly conserved sequence motif that has been identified in various animal and plant species. Chromodomain proteins seem to be either structural components of large macromolecular chromatin complexes or involved in remodelling chromatin structure.
- MACROCHROMATIN BODY
-
(MCB). Discrete accumulation of the histone variant, macroH2A, on the inactive X chromosome.
- CENTROSOME
-
The microtubule organizing centre that divides to organize the two poles of the mitotic spindle and directs assembly of the cytoskeleton, thus controlling cell division, motility and shape.
- EUTHERIANS
-
Mammals that give birth to live offspring (viviparous) and possess an allantoic placenta.
- TROPHECTODERM
-
The precursor to the bulk of the embryonic part of the placenta.
- SEX VESICLE OR XY BODY
-
Pairing of sex chromosomes during meiosis in male mammals is associated with heterochromatinization and occurs in the sex vesicle or XY-body, a specific nuclear structure that can be discerned morphologically.
- ANDROGENONE
-
Embryo with two paternal sets of chromosomes.
- UNIPARENTAL DISOMIC
-
An individual or embryo carrying two chromosomes inherited from the same parent
- LINES
-
Long interspersed nuclear elements (such as L1 repeats) are retroelements present in over 100,000 copies in the mammalian genome.
- REPEAT-INDUCED GENE SILENCING
-
(RIGS). Transgene expression in several organisms may be silenced epigenetically when repeated sequences are present. It has been proposed that interactions between homologous sequences (repeats) might lead to the formation of folded chromatin structures that attract heterochromatin-specific macromolecules
Rights and permissions
About this article
Cite this article
Avner, P., Heard, E. X-chromosome inactivation: counting, choice and initiation. Nat Rev Genet 2, 59–67 (2001). https://doi.org/10.1038/35047580
Issue Date:
DOI: https://doi.org/10.1038/35047580
This article is cited by
-
Unraveling the role of Xist in X chromosome inactivation: insights from rabbit model and deletion analysis of exons and repeat A
Cellular and Molecular Life Sciences (2024)
-
From genotype to phenotype: genetics of mammalian long non-coding RNAs in vivo
Nature Reviews Genetics (2022)
-
Mechanisms of chromatin-based epigenetic inheritance
Science China Life Sciences (2022)
-
The X chromosome and sex-specific effects in infectious disease susceptibility
Human Genomics (2019)
-
A female patient with retinoblastoma and severe intellectual disability carrying an X;13 balanced translocation without rearrangement in the RB1 gene: a case report
BMC Medical Genomics (2019)