Key Points
-
X-chromosome inactivation (XCI) silences one of the two X chromosomes in female mammals to achieve dosage compensation between the sexes.
-
Chromosome-wide silencing is initiated by the long non-coding X-inactivation specific transcript (Xist) RNA, which associates with the inactive X chromosome (Xi) and triggers chromatin modifications and gene silencing.
-
Association of Xist with the Xi leads to the formation of a repressive compartment over genomic repeat sequences within the centre of the Xi territory.
-
Gene silencing requires the repeat A sequence, which is located at the 5′ end of Xist, and silencing factors such as special AT-rich sequence binding protein 1 (SATB1).
-
In development, silencing on the Xi becomes stabilized and does not require continuous Xist expression in somatic cells.
-
DNA methylation and structural-maintenance-of-chromosomes hinge domain containing 1 (SMCHD1) are required for the maintenance of gene repression in somatic cells.
-
The facultative heterochromatin of the Xi is characterized by several chromatin components — including Polycomb group complexes — that make it distinct from other heterochromatin in the cell nucleus.
-
Reactivation of the Xi is observed at certain stages of development, such as in the formation of the female germ cells. It also occurs during experimentally induced reprogramming of induced pluripotent stem cells.
Abstract
In female mammals, one of the two X chromosomes is silenced for dosage compensation between the sexes. X-chromosome inactivation is initiated in early embryogenesis by the Xist RNA that localizes to the inactive X chromosome. During development, the inactive X chromosome is further modified, a specialized form of facultative heterochromatin is formed and gene repression becomes stable and independent of Xist in somatic cells. The recent identification of several factors involved in this process has provided insights into the mechanism of Xist localization and gene silencing. The emerging picture is complex and suggests that chromosome-wide silencing can be partitioned into several steps, the molecular components of which are starting to be defined.
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
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Lyon, M. F. Gene action in the X-chromosome of the mouse (Mus musculus L.). Nature 190, 372–373 (1961).
Barr, M. L. & Bertram, E. G. A morphological distinction between neurones of the male and female, and the behaviour of the nucleolar satellite during accelerated nucleoprotein synthesis. Nature 163, 676 (1949).
Borsani, G. et al. Characterization of a murine gene expressed from the inactive X chromosome. Nature 351, 325–329 (1991).
Brockdorff, N. et al. Conservation of position and exclusive expression of mouse Xist from the inactive X chromosome. Nature 351, 329–331 (1991).
Brown, C. J. et al. A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome. Nature 349, 38–44 (1991).
Clemson, C. M., McNeil, J. A., Willard, H. F. & Lawrence, J. B. XIST RNA paints the inactive X chromosome at interphase: evidence for a novel RNA involved in nuclear/chromosome structure. J. Cell Biol. 132, 259–275 (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).
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).
Augui, S., Nora, E. P. & Heard, E. Regulation of X-chromosome inactivation by the X-inactivation centre. Nature Rev. Genet. 12, 429–442 (2011).
Brown, C. J. & Willard, H. F. The human X-inactivation centre is not required for maintenance of X-chromosome inactivation. Nature 368, 154–156 (1994).
Csankovszki, G., Panning, B., Bates, B., Pehrson, J. R. & Jaenisch, R. Conditional deletion of Xist disrupts histone macroH2A localization but not maintenance of X inactivation. Nature Genet. 22, 323–324 (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).
Cremer, T. & Cremer, M. Chromosome territories. Cold Spring Harb. Perspect. Biol. 2, a003889 (2010).
Zhang, L. F., Huynh, K. D. & Lee, J. T. Perinucleolar targeting of the inactive X during S phase: evidence for a role in the maintenance of silencing. Cell 129, 693–706 (2007).
Wutz, A., Rasmussen, T. P. & Jaenisch, R. Chromosomal silencing and localization are mediated by different domains of Xist RNA. Nature Genet. 30, 167–174 (2002).
Wutz, A. RNAs templating chromatin structure for dosage compensation in animals. Bioessays 25, 434–442 (2003).
Beletskii, A., Hong, Y. K., Pehrson, J., Egholm, M. & Strauss, W. M. PNA interference mapping demonstrates functional domains in the noncoding RNA Xist. Proc. Natl Acad. Sci. USA 98, 9215–9220 (2001).
Sarma, K., Levasseur, P., Aristarkhov, A. & Lee, J. T. Locked nucleic acids (LNAs) reveal sequence requirements and kinetics of Xist RNA localization to the X chromosome. Proc. Natl Acad. Sci. USA 107, 22196–22201 (2011).
Fackelmayer, F. O. A stable proteinaceous structure in the territory of inactive X chromosomes. J. Biol. Chem. 280, 1720–1723 (2005).
Helbig, R. & Fackelmayer, F. O. Scaffold attachment factor A (SAF-A) is concentrated in inactive X chromosome territories through its RGG domain. Chromosoma 112, 173–182 (2003). The identification of SAF-A as a factor enriched in the nuclear scaffold of the Xi.
Pullirsch, D. et al. The Trithorax group protein Ash2l and Saf-A are recruited to the inactive X chromosome at the onset of stable X inactivation. Development 137, 935–943 (2010).
Hasegawa, Y. et al. The matrix protein hnRNP U is required for chromosomal localization of Xist RNA. Dev. Cell 19, 469–476 (2010). This paper demonstrates that SAF-A is required for Xist RNA localization to the Xi in certain cell types.
Chaumeil, J., Le Baccon, P., Wutz, A. & Heard, E. A novel role for Xist RNA in the formation of a repressive nuclear compartment into which genes are recruited when silenced. Genes Dev. 20, 2223–2237 (2006).
Clemson, C. M., Hall, L. L., Byron, M., McNeil, J. & Lawrence, J. B. The X chromosome is organized into a gene-rich outer rim and an internal core containing silenced nongenic sequences. Proc. Natl Acad. Sci. USA 103, 7688–7693 (2006).
Lyon, M. F. X-chromosome inactivation: a repeat hypothesis. Cytogenet. Cell Genet. 80, 133–137 (1998).
Lee, J. T. & Jaenisch, R. Long-range cis effects of ectopic X-inactivation centres on a mouse autosome. Nature 386, 275–279 (1997).
Lee, J. T., Lu, N. & Han, Y. Genetic analysis of the mouse X inactivation center defines an 80-kb multifunction domain. Proc. Natl Acad. Sci. USA 96, 3836–3841 (1999).
Popova, B. C., Tada, T., Takagi, N., Brockdorff, N. & Nesterova, T. B. Attenuated spread of X-inactivation in an X;autosome translocation. Proc. Natl Acad. Sci. USA 103, 7706–7711 (2006).
Tang, Y. A. et al. Efficiency of Xist-mediated silencing on autosomes is linked to chromosomal domain organisation. Epigenetics Chromatin 3, 10 (2010).
Hansen, R. S. X inactivation-specific methylation of LINE-1 elements by DNMT3B: implications for the Lyon repeat hypothesis. Hum. Mol. Genet. 12, 2559–2567 (2003).
Chow, J. C. et al. LINE-1 activity in facultative heterochromatin formation during X chromosome inactivation. Cell 141, 956–969 (2010).
Chow, J. C., Yen, Z., Ziesche, S. M. & Brown, C. J. Silencing of the mammalian X chromosome. Annu. Rev. Genomics Hum. Genet. 6, 69–92 (2005).
Okamoto, I., Otte, A. P., Allis, C. D., Reinberg, D. & Heard, E. Epigenetic dynamics of imprinted X inactivation during early mouse development. Science 303, 644–649 (2004).
Heard, E. et al. Methylation of histone H3 at Lys-9 is an early mark on the X chromosome during X inactivation. Cell 107, 727–738 (2001).
de Napoles, M. et al. Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation. Dev. Cell 7, 663–676 (2004).
Fang, J., Chen, T., Chadwick, B., Li, E. & Zhang, Y. Ring1b-mediated H2A ubiquitination associates with inactive X chromosomes and is involved in initiation of X inactivation. J. Biol. Chem. 279, 52812–52815 (2004).
Plath, K. et al. Role of histone H3 lysine 27 methylation in X inactivation. Science 300, 131–135 (2003).
Leeb, M. & Wutz, A. Ring1B is crucial for the regulation of developmental control genes and PRC1 proteins but not X inactivation in embryonic cells. J. Cell Biol. 178, 219–29 (2007).
Schoeftner, S. et al. Recruitment of PRC1 function at the initiation of X inactivation independent of PRC2 and silencing. EMBO J. 25, 3110–3122 (2006).
Kalantry, S. & Magnuson, T. The Polycomb group protein EED is dispensable for the initiation of random X-chromosome inactivation. PLoS Genet. 2, e66 (2006).
Leeb, M. et al. Polycomb complexes act redundantly to repress genomic repeats and genes. Genes Dev. 24, 265–276 (2010).
Royce-Tolland, M. E. et al. The A-repeat links ASF/SF2-dependent Xist RNA processing with random choice during X inactivation. Nature Struct. Mol. Biol. 17, 948–954 (2010).
Zhao, J., Sun, B. K., Erwin, J. A., Song, J. J. & Lee, J. T. Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome. Science 322, 750–756 (2008).
Maenner, S. et al. 2-D structure of the A region of Xist RNA and its implication for PRC2 association. PLoS Biol. 8, e1000276 (2010).
Kohlmaier, A. et al. A chromosomal memory triggered by Xist regulates histone methylation in X inactivation. PLoS Biol. 2, e171 (2004).
Sado, T., Okano, M., Li, E. & Sasaki, H. De novo DNA methylation is dispensable for the initiation and propagation of X chromosome inactivation. Development 131, 975–982 (2004).
Beard, C., Li, E. & Jaenisch, R. Loss of methylation activates Xist in somatic but not in embryonic cells. Genes Dev. 9, 2325–2334 (1995).
Savarese, F., Flahndorfer, K., Jaenisch, R., Busslinger, M. & Wutz, A. Hematopoietic precursor cells transiently reestablish permissiveness for X inactivation. Mol. Cell. Biol. 26, 7167–7177 (2006).
Agrelo, R. et al. SATB1 defines the developmental context for gene silencing by Xist in lymphoma and embryonic cells. Dev. Cell 16, 507–516 (2009). This study identifies SATB1 as a silencing factor for Xist in cells of a mouse T cell lymphoma model and shows that SATB1 is also expressed in embryonic cells.
Chow, J. C. et al. Inducible XIST-dependent X-chromosome inactivation in human somatic cells is reversible. Proc. Natl Acad. Sci. USA 104, 10104–10109 (2007).
Hall, L. L. et al. An ectopic human XIST gene can induce chromosome inactivation in postdifferentiation human HT-1080 cells. Proc. Natl Acad. Sci. USA 99, 8677–8682 (2002).
Cai, S., Lee, C. C. & Kohwi-Shigematsu, T. SATB1 packages densely looped, transcriptionally active chromatin for coordinated expression of cytokine genes. Nature Genet. 38, 1278–1288 (2006).
Alvarez, J. D. et al. The MAR-binding protein SATB1 orchestrates temporal and spatial expression of multiple genes during T-cell development. Genes Dev. 14, 521–535 (2000).
Galande, S., Purbey, P. K., Notani, D. & Kumar, P. P. The third dimension of gene regulation: organization of dynamic chromatin loopscape by SATB1. Curr. Opin. Genet. Dev. 17, 408–414 (2007).
Notani, D. et al. Global regulator SATB1 recruits β-catenin and regulates T(H)2 differentiation in Wnt-dependent manner. PLoS Biol. 8, e1000296 (2010).
Cotton, A. M. et al. Chromosome-wide DNA methylation analysis predicts human tissue-specific X inactivation. Hum. Genet. 20 May 2011 (doi:10.1007/s00439-011-1007-8).
Hellman, A. & Chess, A. Gene body-specific methylation on the active X chromosome. Science 315, 1141–1143 (2007).
Weber, M. et al. Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells. Nature Genet. 37, 853–862 (2005).
Sado, T. et al. X inactivation in the mouse embryo deficient for Dnmt1: distinct effect of hypomethylation on imprinted and random X inactivation. Dev. Biol. 225, 294–303 (2000).
Blewitt, M. E. et al. An N-ethyl-N-nitrosourea screen for genes involved in variegation in the mouse. Proc. Natl Acad. Sci. USA 102, 7629–7634 (2005).
Blewitt, M. E. et al. SmcHD1, containing a structural-maintenance-of-chromosomes hinge domain, has a critical role in X inactivation. Nature Genet. 40, 663–669 (2008). This paper discusses the identification of Smchd1 as a gene that is required for maintaining gene silencing and DNA methylation on the Xi in mice.
Kanno, T. et al. A structural-maintenance-of-chromosomes hinge domain-containing protein is required for RNA-directed DNA methylation. Nature Genet. 40, 670–675 (2008).
Cotton, A. M. et al. Inactive X chromosome-specific reduction in placental DNA methylation. Hum. Mol. Genet. 18, 3544–3552 (2009).
Wang, J. et al. Imprinted X inactivation maintained by a mouse Polycomb group gene. Nature Genet. 28, 371–375 (2001).
Mak, W. et al. Mitotically stable association of polycomb group proteins eed and enx1 with the inactive X chromosome in trophoblast stem cells. Curr. Biol. 12, 1016–1020 (2002).
Kalantry, S. et al. The Polycomb group protein Eed protects the inactive X-chromosome from differentiation-induced reactivation. Nature Cell Biol. 8, 195–202 (2006).
Csankovszki, G., Nagy, A. & Jaenisch, R. Synergism of Xist RNA, DNA methylation, and histone hypoacetylation in maintaining X chromosome inactivation. J. Cell Biol. 153, 773–784 (2001).
Fodor, B. D., Shukeir, N., Reuter, G. & Jenuwein, T. Mammalian Su(var) genes in chromatin control. Annu. Rev. Cell Dev. Biol. 26, 471–501 (2010).
McStay, B. & Grummt, I. The epigenetics of rRNA genes: from molecular to chromosome biology. Annu. Rev. Cell Dev. Biol. 24, 131–157 (2008).
Costanzi, C. & Pehrson, J. R. Histone macroH2A1 is concentrated in the inactive X chromosome of female mammals. Nature 393, 599–601 (1998).
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).
Changolkar, L. N. et al. Genome-wide distribution of macroH2A1 histone variants in mouse liver chromatin. Mol. Cell Biol. 30, 5473–5483 (2010).
Marks, H. et al. High-resolution analysis of epigenetic changes associated with X inactivation. Genome Res. 19, 1361–1373 (2009).
Mietton, F. et al. Weak but uniform enrichment of the histone variant macroH2A1 along the inactive X chromosome. Mol. Cell Biol. 29, 150–156 (2009).
Chadwick, B. P. & Willard, H. F. Multiple spatially distinct types of facultative heterochromatin on the human inactive X chromosome. Proc. Natl Acad. Sci. USA 101, 17450–17455 (2004).
Chaumeil, J., Okamoto, I., Guggiari, M. & Heard, E. Integrated kinetics of X chromosome inactivation in differentiating embryonic stem cells. Cytogenet. Genome Res. 99, 75–84 (2002).
Keohane, A. M., O' Neill L, P., Belyaev, N. D., Lavender, J. S. & Turner, B. M. X-inactivation and histone H4 acetylation in embryonic stem cells. Dev. Biol. 180, 618–630 (1996).
Mermoud, J. E., Costanzi, C., Pehrson, J. R. & Brockdorff, N. Histone macroH2A1.2 relocates to the inactive X chromosome after initiation and propagation of X-inactivation. J. Cell Biol. 147, 1399–1408 (1999).
Plath, K. et al. Developmentally regulated alterations in Polycomb repressive complex 1 proteins on the inactive X chromosome. J. Cell Biol. 167, 1025–1035 (2004).
Hernandez-Munoz, I. et al. Stable X chromosome inactivation involves the PRC1 Polycomb complex and requires histone MACROH2A1 and the CULLIN3/SPOP ubiquitin E3 ligase. Proc. Natl Acad. Sci. USA 102, 7635–7640 (2005).
Changolkar, L. N., Singh, G. & Pehrson, J. R. macroH2A1-dependent silencing of endogenous murine leukemia viruses. Mol. Cell Biol. 28, 2059–2065 (2008).
Chuva de Sousa Lopes, S. M. et al. X chromosome activity in mouse XX primordial germ cells. PLoS Genet. 4, e30 (2008).
Sugimoto, M. & Abe, K. X chromosome reactivation initiates in nascent primordial germ cells in mice. PLoS Genet. 3, e116 (2007).
Tam, P. P., Zhou, S. X. & Tan, S. S. X-chromosome activity of the mouse primordial germ cells revealed by the expression of an X-linked lacZ transgene. Development 120, 2925–2932 (1994).
Mak, W. et al. Reactivation of the paternal X chromosome in early mouse embryos. Science 303, 666–669 (2004).
Takagi, N., Yoshida, M. A., Sugawara, O. & Sasaki, M. Reversal of X-inactivation in female mouse somatic cells hybridized with murine teratocarcinoma stem cells in vitro. Cell 34, 1053–1062 (1983).
Ying, Q. L., Nichols, J., Evans, E. P. & Smith, A. G. Changing potency by spontaneous fusion. Nature 416, 545–548 (2002).
Maherali, N. et al. Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell 1, 55–70 (2007).
Navarro, P. et al. Molecular coupling of Xist regulation and pluripotency. Science 321, 1693–1695 (2008). This paper reports a binding site for OCT4 within the first intron of the Xist gene and implicates it in the repression of Xist in pluripotent mouse ESCs.
Donohoe, M. E., Silva, S. S., Pinter, S. F., Xu, N. & Lee, J. T. The pluripotency factor Oct4 interacts with Ctcf and also controls X-chromosome pairing and counting. Nature 460, 128–132 (2009). This study identifies the OCT4 binding site in the first intron of the Xist gene and within the promoter and enhancer region of the Tsix gene, suggesting that these contribute to the regulation of Xist in mouse ESCs.
Navarro, P. et al. Molecular coupling of Tsix regulation and pluripotency. Nature 468, 457–460 (2010). This study observes that Tsix is regulated by the transcription factor REX1 but not OCT4. The results are in conflict with those in reference 90.
Masui, S. et al. Rex1/Zfp42 is dispensable for pluripotency in mouse ES cells. BMC Dev. Biol. 8, 45 (2008).
Barakat, T. S. et al. RNF12 activates Xist and is essential for X chromosome inactivation. PLoS Genet. 7, e1002001 (2011).
Guo, G. et al. Klf4 reverts developmentally programmed restriction of ground state pluripotency. Development 136, 1063–1069 (2009).
Lengner, C. J. et al. Derivation of pre-X inactivation human embryonic stem cells under physiological oxygen concentrations. Cell 141, 872–883 (2010).
Inoue, K. et al. Impeding Xist expression from the active X chromosome improves mouse somatic cell nuclear transfer. Science 330, 496–499 (2010). This paper shows that Xist is aberrantly activated in nuclear transfer mouse embryos. The authors show that the frequency of obtaining cloned mice can be elevated tenfold by using a deletion of the Xist gene.
Cobb, S., Guy, J. & Bird, A. Reversibility of functional deficits in experimental models of Rett syndrome. Biochem. Soc. Trans. 38, 498–506 (2010).
Hall, L. L., Byron, M., Pageau, G. & Lawrence, J. B. AURKB-mediated effects on chromatin regulate binding versus release of XIST RNA to the inactive chromosome. J. Cell Biol. 186, 491–507 (2009).
Huarte, M. et al. A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response. Cell 142, 409–419 (2010).
Rinn, J. L. et al. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 129, 1311–1323 (2007).
Terranova, R. et al. Polycomb group proteins Ezh2 and Rnf2 direct genomic contraction and imprinted repression in early mouse embryos. Dev. Cell 15, 668–679 (2008).
Redrup, L. et al. The long noncoding RNA Kcnq1ot1 organises a lineage-specific nuclear domain for epigenetic gene silencing. Development 136, 525–530 (2009).
Pandey, R. R. et al. Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation. Mol. Cell 32, 232–246 (2008).
Khalil, A. M. et al. Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc. Natl Acad. Sci. USA 106, 11667–11672 (2009).
Carrel, L. & Willard, H. F. X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 434, 400–404 (2005).
Filippova, G. N. et al. Boundaries between chromosomal domains of X inactivation and escape bind CTCF and lack CpG methylation during early development. Dev. Cell 8, 31–42 (2005).
Li, N. & Carrel, L. Escape from X chromosome inactivation is an intrinsic property of the Jarid1c locus. Proc. Natl Acad. Sci. USA 105, 17055–17060 (2008).
Hadjantonakis, A. K., Cox, L. L., Tam, P. P. & Nagy, A. An X-linked GFP transgene reveals unexpected paternal X-chromosome activity in trophoblastic giant cells of the mouse placenta. Genesis 29, 133–140 (2001).
Hoki, Y. et al. Incomplete X-inactivation initiated by a hypomorphic Xist allele in the mouse. Development 138, 2649–2659 (2011).
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).
Okamoto, I. et al. Eutherian mammals use diverse strategies to initiate X-chromosome inactivation during development. Nature 474, 239–240 (2011). This paper investigates XCI in rabbit and human embryos and suggests that different mammals use different strategies.
van den Berg, I. M. J. et al. X chromosome inactivation is initiated in human preimplantation embryos. Am. J. Hum. Genet. 84, 771–779 (2009). This study examines XCI in human embryos.
Duret, L., Chureau, C., Samain, S., Weissenbach, J. & Avner, P. The Xist RNA gene evolved in eutherians by pseudogenization of a protein-coding gene. Science 312, 1653–1655 (2006).
Hore, T. A., Rapkins, R. W. & Graves, J. A. Construction and evolution of imprinted loci in mammals. Trends Genet. 23, 440–448 (2007).
Al Nadaf, S. et al. Activity map of the tammar X chromosome shows that marsupial X inactivation is incomplete and escape is stochastic. Genome Biol. 11, R122 (2010).
Koina, E., Chaumeil, J., Greaves, I. K., Tremethick, D. J. & Graves, J. A. Specific patterns of histone marks accompany X chromosome inactivation in a marsupial. Chromosome Res. 17, 115–126 (2009).
Mahadevaiah, S. K. et al. Key features of the X inactivation process are conserved between marsupials and eutherians. Curr. Biol. 19, 1478–1484 (2009).
Rens, W., Wallduck, M. S., Lovell, F. L., Ferguson-Smith, M. A. & Ferguson-Smith, A. C. Epigenetic modifications on X chromosomes in marsupial and monotreme mammals and implications for evolution of dosage compensation. Proc. Natl Acad. Sci. USA 107, 17657–17662 (2010).
Zakharova, I. S. et al. Histone H3 trimethylation at lysine 9 marks the inactive metaphase X chromosome in the marsupial Monodelphis domestica. Chromosoma 120, 177–183 (2011).
Takagi, N. & Sasaki, M. Preferential inactivation of the paternally derived X chromosome in the extraembryonic membranes of the mouse. Nature 256, 640–642 (1975).
Jonkers, I. et al. Xist RNA is confined to the nuclear territory of the silenced X chromosome throughout the cell cycle. Mol. Cell Biol. 28, 5583–5594 (2008).
Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).
Okita, K., Ichisaka, T. & Yamanaka, S. Generation of germline-competent induced pluripotent stem cells. Nature 448, 313–317 (2007).
Wernig, M. et al. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448, 318–324 (2007).
Han, D. W. et al. Direct reprogramming of fibroblasts into epiblast stem cells. Nature Cell Biol. 13, 66–71 (2011).
Casanova, M. et al. Polycomblike 2 facilitates the recruitment of PRC2 Polycomb group complexes to the inactive X chromosome and to target loci in embryonic stem cells. Development 138, 1471–1482 (2011).
Acknowledgements
The author is the recipient of a Wellcome Trust Senior Research Fellowship (grant reference 087530/Z/08/A).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The author declares no competing financial interests.
Related links
Glossary
- Dosage compensation
-
In mammals, the difference in chromosome complement between XY males and XX females is compensated by transcriptional silencing of genes on one of the two X chromosomes in female cells. Therefore, in both male and female cells, a single copy of each of the X-linked genes is active; this is in contrast to autosomal genes, which are expressed from two homologous chromosomes.
- Facultative heterochromatin
-
A subtype of heterochromatin that is formed in the euchromatic environment, in which heterochromatin proteins are used to stably repress the activity of certain target genes.
- Chromosome territory
-
The volume occupied by the DNA of a single chromosome in the interphase cell nucleus.
- Polycomb group complex
-
(PcG complex). A chromatin-modifying complex that contains proteins that were originally indentified as being required for maintenance of homeotic gene silencing in Drosophila melanogaster.
- Nuclear scaffold
-
A network within the nucleus consisting of RNA and protein that is believed to organize chromatin.
- Long interspersed elements
-
(LINEs). Types of repetitive DNA in animal genomes that are derived from transposons.
- Blastocysts
-
Pre-implantation embryonic stages that are characterized by the first definitive lineages. They consist of a fluid-filled cavity (blastocoel), a focal cluster of cells from which the embryo will develop (inner cell mass) and peripheral trophoblast cells, which form the placenta.
- Pericentric heterochromatin
-
A block of heterochromatin-containing silent repeats surrounding the centromeres of the chromosomes.
- Thymocytes
-
A subset of white blood cells (T cells) that reside in the thymus. Thymocytes perform functions in the immune response.
- Imprinted XCI
-
(Imprinted X-chromosome inactivation). Inactivation of the paternally inherited X chromosome, whereby inactivation is determined by the parental origin of the chromosome.
- Trophoblast
-
An extra-embryonic lineage that is derived from the trophectoderm of the blastocyst, which gives rise to a cell layer of the placenta.
- Histone variant
-
A protein that contains a histone domain and, in addition, another unrelated protein domain.
- Trithorax protein
-
A protein that maintains the stable and heritable active state of several genes, including the homeotic genes. Trithorax group proteins were discovered in genetic screens in Drosophila melanogaster, in which they were found to oppose the silencing mediated by Polycomb group complexes.
- Primordial germ cells
-
Embryonic cells that give rise to germ cells from which the haploid gametes (oocytes in females and sperm in males) differentiate.
- Inner cell mass
-
A small clump of cells in the blastocyst, which gives rise to the entire fetus plus some of its extra-embryonic membranes.
- Pluripotent
-
A term used to describe a cell that has the developmental potential to differentiate into all lineages of the embryo, including the germ cells.
- Epiblast
-
A term for the group of embryonic cells from which the embryo is structured during gastrulation. It is derived from the inner cell mass of the blastocyst.
Rights and permissions
About this article
Cite this article
Wutz, A. Gene silencing in X-chromosome inactivation: advances in understanding facultative heterochromatin formation. Nat Rev Genet 12, 542–553 (2011). https://doi.org/10.1038/nrg3035
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrg3035
This article is cited by
-
The transcriptional legacy of developmental stochasticity
Nature Communications (2023)
-
An emerging link between lncRNAs and cancer sex dimorphism
Human Genetics (2023)
-
Skewed X-chromosome Inactivation in Women with Idiopathic Intellectual Disability is Indicative of Pathogenic Variants
Molecular Neurobiology (2023)
-
The landscape of promoter-centred RNA–DNA interactions in rice
Nature Plants (2022)
-
A comprehensive review of long non-coding RNAs in the pathogenesis and development of non-alcoholic fatty liver disease
Nutrition & Metabolism (2021)