Home LiteratureArticle Details
PMID: 21765457 Published · epublish English Journal Article Research Support, Non-U.S. Gov't Review

Gene silencing in X-chromosome inactivation: advances in understanding facultative heterochromatin formation.

Nature reviews. Genetics ·Vol. 12 ·No. 8 ·2011-07-18 ·Pages 542-53

Wutz A

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.

MeSH Terms
Animals Chromatin Assembly and Disassembly Dosage Compensation, Genetic Embryonic Development/genetics Female Gene Silencing Heterochromatin/metabolism Humans RNA, Long Noncoding RNA, Untranslated/genetics Sequence Analysis, RNA X Chromosome X Chromosome Inactivation
Chemicals
Heterochromatin RNA, Long Noncoding RNA, Untranslated XIST non-coding RNA
Authors & Affiliations
1 authors, click to expand affiliations / ORCID
Wutz Anton
Wellcome Trust Centre for Stem Cell Research, Cambridge, UK. [email protected]
References (125)
125 references, click to expand
  1. Global regulator SATB1 recruits beta-catenin and regulates T(H)2 differentiation in Wnt-dependent manner.
    PLoS Biol. 2010 Jan 26;8(1):e1000296 PMID: 20126258
  2. The Trithorax group protein Ash2l and Saf-A are recruited to the inactive X chromosome at the onset of stable X inactivation.
    Development. 2010 Mar;137(6):935-43 PMID: 20150277
  3. A shift from reversible to irreversible X inactivation is triggered during ES cell differentiation.
    Mol Cell. 2000 Apr;5(4):695-705 PMID: 10882105
  4. Mitotically stable association of polycomb group proteins eed and enx1 with the inactive x chromosome in trophoblast stem cells.
    Curr Biol. 2002 Jun 25;12(12):1016-20 PMID: 12123576
  5. Hematopoietic precursor cells transiently reestablish permissiveness for X inactivation.
    Mol Cell Biol. 2006 Oct;26(19):7167-77 PMID: 16980619
  6. Imprinted X inactivation maintained by a mouse Polycomb group gene.
    Nat Genet. 2001 Aug;28(4):371-5 PMID: 11479595
  7. Generation of germline-competent induced pluripotent stem cells.
    Nature. 2007 Jul 19;448(7151):313-7 PMID: 17554338
  8. The human X-inactivation centre is not required for maintenance of X-chromosome inactivation.
    Nature. 1994 Mar 10;368(6467):154-6 PMID: 8139659
  9. X-Inactivation and histone H4 acetylation in embryonic stem cells.
    Dev Biol. 1996 Dec 15;180(2):618-30 PMID: 8954732
  10. Loss of methylation activates Xist in somatic but not in embryonic cells.
    Genes Dev. 1995 Oct 1;9(19):2325-34 PMID: 7557385
  11. The long noncoding RNA Kcnq1ot1 organises a lineage-specific nuclear domain for epigenetic gene silencing.
    Development. 2009 Feb;136(4):525-30 PMID: 19144718
  12. Reactivation of the paternal X chromosome in early mouse embryos.
    Science. 2004 Jan 30;303(5658):666-9 PMID: 14752160
  13. An ectopic human XIST gene can induce chromosome inactivation in postdifferentiation human HT-1080 cells.
    Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8677-82 PMID: 12072569
  14. The MAR-binding protein SATB1 orchestrates temporal and spatial expression of multiple genes during T-cell development.
    Genes Dev. 2000 Mar 1;14(5):521-35 PMID: 10716941
  15. The epigenetics of rRNA genes: from molecular to chromosome biology.
    Annu Rev Cell Dev Biol. 2008;24:131-57 PMID: 18616426
  16. 2-D structure of the A region of Xist RNA and its implication for PRC2 association.
    PLoS Biol. 2010 Jan;8(1):e1000276 PMID: 20052282
  17. Conditional deletion of Xist disrupts histone macroH2A localization but not maintenance of X inactivation.
    Nat Genet. 1999 Aug;22(4):323-4 PMID: 10431231
  18. XIST RNA paints the inactive X chromosome at interphase: evidence for a novel RNA involved in nuclear/chromosome structure.
    J Cell Biol. 1996 Feb;132(3):259-75 PMID: 8636206
  19. The matrix protein hnRNP U is required for chromosomal localization of Xist RNA.
    Dev Cell. 2010 Sep 14;19(3):469-76 PMID: 20833368
  20. Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression.
    Proc Natl Acad Sci U S A. 2009 Jul 14;106(28):11667-72 PMID: 19571010
  21. Key features of the X inactivation process are conserved between marsupials and eutherians.
    Curr Biol. 2009 Sep 15;19(17):1478-84 PMID: 19716301
  22. Ring1b-mediated H2A ubiquitination associates with inactive X chromosomes and is involved in initiation of X inactivation.
    J Biol Chem. 2004 Dec 17;279(51):52812-5 PMID: 15509584
  23. The Polycomb group protein Eed protects the inactive X-chromosome from differentiation-induced reactivation.
    Nat Cell Biol. 2006 Feb;8(2):195-202 PMID: 16415857
  24. Polycomb group proteins Ezh2 and Rnf2 direct genomic contraction and imprinted repression in early mouse embryos.
    Dev Cell. 2008 Nov;15(5):668-79 PMID: 18848501
  25. A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response.
    Cell. 2010 Aug 6;142(3):409-19 PMID: 20673990
  26. Inducible XIST-dependent X-chromosome inactivation in human somatic cells is reversible.
    Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10104-9 PMID: 17537922
  27. Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation.
    Dev Cell. 2004 Nov;7(5):663-76 PMID: 15525528
  28. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.
    Cell. 2006 Aug 25;126(4):663-76 PMID: 16904174
  29. The inactive X chromosome in female mammals is distinguished by a lack of histone H4 acetylation, a cytogenetic marker for gene expression.
    Cell. 1993 Jul 30;74(2):281-9 PMID: 8343956
  30. Reversal of X-inactivation in female mouse somatic cells hybridized with murine teratocarcinoma stem cells in vitro.
    Cell. 1983 Oct;34(3):1053-62 PMID: 6627391
  31. An N-ethyl-N-nitrosourea screen for genes involved in variegation in the mouse.
    Proc Natl Acad Sci U S A. 2005 May 24;102(21):7629-34 PMID: 15890782
  32. Genome-wide distribution of macroH2A1 histone variants in mouse liver chromatin.
    Mol Cell Biol. 2010 Dec;30(23):5473-83 PMID: 20937776
  33. Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells.
    Nat Genet. 2005 Aug;37(8):853-62 PMID: 16007088
  34. Stable X chromosome inactivation involves the PRC1 Polycomb complex and requires histone MACROH2A1 and the CULLIN3/SPOP ubiquitin E3 ligase.
    Proc Natl Acad Sci U S A. 2005 May 24;102(21):7635-40 PMID: 15897469
  35. AURKB-mediated effects on chromatin regulate binding versus release of XIST RNA to the inactive chromosome.
    J Cell Biol. 2009 Aug 24;186(4):491-507 PMID: 19704020
  36. X inactivation-specific methylation of LINE-1 elements by DNMT3B: implications for the Lyon repeat hypothesis.
    Hum Mol Genet. 2003 Oct 1;12(19):2559-67 PMID: 12925568
  37. Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution.
    Cell Stem Cell. 2007 Jun 7;1(1):55-70 PMID: 18371336
  38. A novel role for Xist RNA in the formation of a repressive nuclear compartment into which genes are recruited when silenced.
    Genes Dev. 2006 Aug 15;20(16):2223-37 PMID: 16912274
  39. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state.
    Nature. 2007 Jul 19;448(7151):318-24 PMID: 17554336
  40. Recruitment of PRC1 function at the initiation of X inactivation independent of PRC2 and silencing.
    EMBO J. 2006 Jul 12;25(13):3110-22 PMID: 16763550
  41. Histone macroH2A1 is concentrated in the inactive X chromosome of female mammals.
    Nature. 1998 Jun 11;393(6685):599-601 PMID: 9634239
  42. Requirement for Xist in X chromosome inactivation.
    Nature. 1996 Jan 11;379(6561):131-7 PMID: 8538762
  43. The X chromosome is organized into a gene-rich outer rim and an internal core containing silenced nongenic sequences.
    Proc Natl Acad Sci U S A. 2006 May 16;103(20):7688-93 PMID: 16682630
  44. Efficiency of Xist-mediated silencing on autosomes is linked to chromosomal domain organisation.
    Epigenetics Chromatin. 2010 May 07;3(1):10 PMID: 20459652
  45. Histone H3 trimethylation at lysine 9 marks the inactive metaphase X chromosome in the marsupial Monodelphis domestica.
    Chromosoma. 2011 Apr;120(2):177-83 PMID: 21110203
  46. Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation.
    Mol Cell. 2008 Oct 24;32(2):232-46 PMID: 18951091
  47. Weak but uniform enrichment of the histone variant macroH2A1 along the inactive X chromosome.
    Mol Cell Biol. 2009 Jan;29(1):150-6 PMID: 18936163
  48. Changing potency by spontaneous fusion.
    Nature. 2002 Apr 4;416(6880):545-8 PMID: 11932748
  49. Locked nucleic acids (LNAs) reveal sequence requirements and kinetics of Xist RNA localization to the X chromosome.
    Proc Natl Acad Sci U S A. 2010 Dec 21;107(51):22196-201 PMID: 21135235
  50. Integrated kinetics of X chromosome inactivation in differentiating embryonic stem cells.
    Cytogenet Genome Res. 2002;99(1-4):75-84 PMID: 12900548
  51. A chromosomal memory triggered by Xist regulates histone methylation in X inactivation.
    PLoS Biol. 2004 Jul;2(7):E171 PMID: 15252442
  52. Synergism of Xist RNA, DNA methylation, and histone hypoacetylation in maintaining X chromosome inactivation.
    J Cell Biol. 2001 May 14;153(4):773-84 PMID: 11352938
  53. Specific patterns of histone marks accompany X chromosome inactivation in a marsupial.
    Chromosome Res. 2009;17(1):115-26 PMID: 19214764
  54. The third dimension of gene regulation: organization of dynamic chromatin loopscape by SATB1.
    Curr Opin Genet Dev. 2007 Oct;17(5):408-14 PMID: 17913490
  55. A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome.
    Nature. 1991 Jan 3;349(6304):38-44 PMID: 1985261
  56. Reversibility of functional deficits in experimental models of Rett syndrome.
    Biochem Soc Trans. 2010 Apr;38(2):498-506 PMID: 20298210
  57. The Xist RNA gene evolved in eutherians by pseudogenization of a protein-coding gene.
    Science. 2006 Jun 16;312(5780):1653-5 PMID: 16778056
  58. Developmentally regulated alterations in Polycomb repressive complex 1 proteins on the inactive X chromosome.
    J Cell Biol. 2004 Dec 20;167(6):1025-35 PMID: 15596546
  59. Xist RNA is confined to the nuclear territory of the silenced X chromosome throughout the cell cycle.
    Mol Cell Biol. 2008 Sep;28(18):5583-94 PMID: 18625719
  60. Gene action in the X-chromosome of the mouse (Mus musculus L.).
    Nature. 1961 Apr 22;190:372-3 PMID: 13764598
  61. RNF12 activates Xist and is essential for X chromosome inactivation.
    PLoS Genet. 2011 Jan 27;7(1):e1002001 PMID: 21298085
  62. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs.
    Cell. 2007 Jun 29;129(7):1311-23 PMID: 17604720
  63. Direct reprogramming of fibroblasts into epiblast stem cells.
    Nat Cell Biol. 2011 Jan;13(1):66-71 PMID: 21131959
  64. Ring1B is crucial for the regulation of developmental control genes and PRC1 proteins but not X inactivation in embryonic cells.
    J Cell Biol. 2007 Jul 16;178(2):219-29 PMID: 17620408
  65. Regulation of X-chromosome inactivation by the X-inactivation centre.
    Nat Rev Genet. 2011 Jun;12(6):429-42 PMID: 21587299
  66. SmcHD1, containing a structural-maintenance-of-chromosomes hinge domain, has a critical role in X inactivation.
    Nat Genet. 2008 May;40(5):663-9 PMID: 18425126
  67. X chromosome reactivation initiates in nascent primordial germ cells in mice.
    PLoS Genet. 2007 Jul;3(7):e116 PMID: 17676999
  68. An X-linked GFP transgene reveals unexpected paternal X-chromosome activity in trophoblastic giant cells of the mouse placenta.
    Genesis. 2001 Mar;29(3):133-40 PMID: 11252054
  69. The Polycomb group protein EED is dispensable for the initiation of random X-chromosome inactivation.
    PLoS Genet. 2006 May;2(5):e66 PMID: 16680199
  70. Chromosome territories.
    Cold Spring Harb Perspect Biol. 2010 Mar;2(3):a003889 PMID: 20300217
  71. Multiple spatially distinct types of facultative heterochromatin on the human inactive X chromosome.
    Proc Natl Acad Sci U S A. 2004 Dec 14;101(50):17450-5 PMID: 15574503
  72. Long-range cis effects of ectopic X-inactivation centres on a mouse autosome.
    Nature. 1997 Mar 20;386(6622):275-9 PMID: 9069285
  73. Perinucleolar targeting of the inactive X during S phase: evidence for a role in the maintenance of silencing.
    Cell. 2007 May 18;129(4):693-706 PMID: 17512404
  74. Rex1/Zfp42 is dispensable for pluripotency in mouse ES cells.
    BMC Dev Biol. 2008 Apr 24;8:45 PMID: 18433507
  75. Scaffold attachment factor A (SAF-A) is concentrated in inactive X chromosome territories through its RGG domain.
    Chromosoma. 2003 Dec;112(4):173-82 PMID: 14608463
  76. Xist RNA exhibits a banded localization on the inactive X chromosome and is excluded from autosomal material in cis.
    Hum Mol Genet. 1999 Feb;8(2):195-204 PMID: 9931327
  77. Chromosomal silencing and localization are mediated by different domains of Xist RNA.
    Nat Genet. 2002 Feb;30(2):167-74 PMID: 11780141
  78. Gene body-specific methylation on the active X chromosome.
    Science. 2007 Feb 23;315(5815):1141-3 PMID: 17322062
  79. Construction and evolution of imprinted loci in mammals.
    Trends Genet. 2007 Sep;23(9):440-8 PMID: 17683825
  80. Derivation of pre-X inactivation human embryonic stem cells under physiological oxygen concentrations.
    Cell. 2010 May 28;141(5):872-83 PMID: 20471072
  81. Incomplete X-inactivation initiated by a hypomorphic Xist allele in the mouse.
    Development. 2011 Jul;138(13):2649-59 PMID: 21613321
  82. De novo DNA methylation is dispensable for the initiation and propagation of X chromosome inactivation.
    Development. 2004 Mar;131(5):975-82 PMID: 14973270
  83. Genetic analysis of the mouse X inactivation center defines an 80-kb multifunction domain.
    Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3836-41 PMID: 10097124
  84. macroH2A1-dependent silencing of endogenous murine leukemia viruses.
    Mol Cell Biol. 2008 Mar;28(6):2059-65 PMID: 18195046
  85. A structural-maintenance-of-chromosomes hinge domain-containing protein is required for RNA-directed DNA methylation.
    Nat Genet. 2008 May;40(5):670-5 PMID: 18425128
  86. Characterization of a murine gene expressed from the inactive X chromosome.
    Nature. 1991 May 23;351(6324):325-9 PMID: 2034278
  87. X-chromosome activity of the mouse primordial germ cells revealed by the expression of an X-linked lacZ transgene.
    Development. 1994 Oct;120(10):2925-32 PMID: 7607082
  88. SATB1 packages densely looped, transcriptionally active chromatin for coordinated expression of cytokine genes.
    Nat Genet. 2006 Nov;38(11):1278-88 PMID: 17057718
  89. The pluripotency factor Oct4 interacts with Ctcf and also controls X-chromosome pairing and counting.
    Nature. 2009 Jul 2;460(7251):128-32 PMID: 19536159
  90. X-chromosome inactivation: a repeat hypothesis.
    Cytogenet Cell Genet. 1998;80(1-4):133-7 PMID: 9678347
  91. Mammalian Su(var) genes in chromatin control.
    Annu Rev Cell Dev Biol. 2010;26:471-501 PMID: 19575672
  92. X chromosome inactivation is initiated in human preimplantation embryos.
    Am J Hum Genet. 2009 Jun;84(6):771-9 PMID: 19481196
  93. The A-repeat links ASF/SF2-dependent Xist RNA processing with random choice during X inactivation.
    Nat Struct Mol Biol. 2010 Aug;17(8):948-54 PMID: 20657585
  94. Xist-deficient mice are defective in dosage compensation but not spermatogenesis.
    Genes Dev. 1997 Jan 15;11(2):156-66 PMID: 9009199
  95. Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome.
    Science. 2008 Oct 31;322(5902):750-6 PMID: 18974356
  96. Histone macroH2A1.2 relocates to the inactive X chromosome after initiation and propagation of X-inactivation.
    J Cell Biol. 1999 Dec 27;147(7):1399-408 PMID: 10613899
  97. Klf4 reverts developmentally programmed restriction of ground state pluripotency.
    Development. 2009 Apr;136(7):1063-9 PMID: 19224983
  98. Polycomblike 2 facilitates the recruitment of PRC2 Polycomb group complexes to the inactive X chromosome and to target loci in embryonic stem cells.
    Development. 2011 Apr;138(8):1471-82 PMID: 21367819
  99. X inactivation in the mouse embryo deficient for Dnmt1: distinct effect of hypomethylation on imprinted and random X inactivation.
    Dev Biol. 2000 Sep 15;225(2):294-303 PMID: 10985851
  100. Role of histone H3 lysine 27 methylation in X inactivation.
    Science. 2003 Apr 4;300(5616):131-5 PMID: 12649488
  101. High-resolution analysis of epigenetic changes associated with X inactivation.
    Genome Res. 2009 Aug;19(8):1361-73 PMID: 19581487
  102. A stable proteinaceous structure in the territory of inactive X chromosomes.
    J Biol Chem. 2005 Jan 21;280(3):1720-3 PMID: 15563465
  103. Chromosome-wide DNA methylation analysis predicts human tissue-specific X inactivation.
    Hum Genet. 2011 Aug;130(2):187-201 PMID: 21597963
  104. Attenuated spread of X-inactivation in an X;autosome translocation.
    Proc Natl Acad Sci U S A. 2006 May 16;103(20):7706-11 PMID: 16679409
  105. Impeding Xist expression from the active X chromosome improves mouse somatic cell nuclear transfer.
    Science. 2010 Oct 22;330(6003):496-9 PMID: 20847234
  106. PNA interference mapping demonstrates functional domains in the noncoding RNA Xist.
    Proc Natl Acad Sci U S A. 2001 Jul 31;98(16):9215-20 PMID: 11481485
  107. Preferential inactivation of the paternally derived X chromosome in the extraembryonic membranes of the mouse.
    Nature. 1975 Aug 21;256(5519):640-2 PMID: 1152998
  108. Inactive X chromosome-specific reduction in placental DNA methylation.
    Hum Mol Genet. 2009 Oct 1;18(19):3544-52 PMID: 19586922
  109. Epigenetic modifications on X chromosomes in marsupial and monotreme mammals and implications for evolution of dosage compensation.
    Proc Natl Acad Sci U S A. 2010 Oct 12;107(41):17657-62 PMID: 20861449
  110. Activity map of the tammar X chromosome shows that marsupial X inactivation is incomplete and escape is stochastic.
    Genome Biol. 2010;11(12):R122 PMID: 21182760
  111. Silencing of the mammalian X chromosome.
    Annu Rev Genomics Hum Genet. 2005;6:69-92 PMID: 16124854
  112. Molecular coupling of Tsix regulation and pluripotency.
    Nature. 2010 Nov 18;468(7322):457-60 PMID: 21085182
  113. SATB1 defines the developmental context for gene silencing by Xist in lymphoma and embryonic cells.
    Dev Cell. 2009 Apr;16(4):507-16 PMID: 19386260
  114. Escape from X chromosome inactivation is an intrinsic property of the Jarid1c locus.
    Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):17055-60 PMID: 18971342
  115. Epigenetic dynamics of imprinted X inactivation during early mouse development.
    Science. 2004 Jan 30;303(5658):644-9 PMID: 14671313
  116. X chromosome activity in mouse XX primordial germ cells.
    PLoS Genet. 2008 Feb;4(2):e30 PMID: 18266475
  117. A morphological distinction between neurones of the male and female, and the behaviour of the nucleolar satellite during accelerated nucleoprotein synthesis.
    Nature. 1949 Apr 30;163(4148):676 PMID: 18120749
  118. Molecular coupling of Xist regulation and pluripotency.
    Science. 2008 Sep 19;321(5896):1693-5 PMID: 18802003
  119. RNAs templating chromatin structure for dosage compensation in animals.
    Bioessays. 2003 May;25(5):434-42 PMID: 12717814
  120. LINE-1 activity in facultative heterochromatin formation during X chromosome inactivation.
    Cell. 2010 Jun 11;141(6):956-69 PMID: 20550932
  121. X-inactivation profile reveals extensive variability in X-linked gene expression in females.
    Nature. 2005 Mar 17;434(7031):400-4 PMID: 15772666
  122. Conservation of position and exclusive expression of mouse Xist from the inactive X chromosome.
    Nature. 1991 May 23;351(6324):329-31 PMID: 2034279
  123. Methylation of histone H3 at Lys-9 is an early mark on the X chromosome during X inactivation.
    Cell. 2001 Dec 14;107(6):727-38 PMID: 11747809
  124. Boundaries between chromosomal domains of X inactivation and escape bind CTCF and lack CpG methylation during early development.
    Dev Cell. 2005 Jan;8(1):31-42 PMID: 15669143
  125. Polycomb complexes act redundantly to repress genomic repeats and genes.
    Genes Dev. 2010 Feb 1;24(3):265-76 PMID: 20123906
Article Info
Journal
Nature reviews. Genetics
Abbr.
Nat Rev Genet
ISSN
1471-0064
DOI
10.1038/nrg3035
Email
[email protected]
Published
2011-07-18
Epub
2011-00-18
Pages
542-53
Language
English
Region
England
NLM ID
100962779
Subset
IM
Grants
Wellcome Trust · 087530 · United Kingdom
Medical Research Council · G0800784 · United Kingdom
Wellcome Trust · 087530/Z/08/A · United Kingdom
External Links
PubMed source DOI: 10.1038/nrg3035 View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2