Skip to main content

Advertisement

SpringerLink
Log in

Epigenetic and LncRNA-Mediated Regulation of X Chromosome Inactivation and Its Impact on Pathogenesis

  • RNA in Pathobiology (AW Duncan, Section Editor)
  • Published:
Current Pathobiology Reports

Abstract

Purpose of Review

In multicellular organisms, development of genetic sex determination leads to gene dosage imbalances between the sex chromosomes and the autosomes and between the sexes. In mammals with XY-based system, a dosage compensation mechanism called X chromosome inactivation (XCI) balances gene expression from unequal number of sex chromosomes between the homogametic (XX) females and heterogametic (XY) males. XCI-mediated dosage compensation involves transcriptional silencing of one of the two X chromosomes in female cells and is tightly mediated during early development.

Recent Findings

The silencing mechanism relies on coordinated action of several epigenetic mechanisms that include imprinting, long noncoding RNA (lncRNA)-mediated chromatin regulation, and nuclear organization. Alterations in the establishment and maintenance of XCI have been associated with female-specific developmental defects, X-linked diseases, and cancer.

Summary

In this review, we discuss the current understanding on the epigenetic and lncRNA-mediated regulation of XCI and how alterations in XCI are linked to developmental defects and diseases such as cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Recently Published Papers of Particular Interest Have Been Highlighted as: • Of importance

  1. Moore KL, Barr ML (1953) Morphology of the nerve cell nucleus in mammals, with special reference to the sex chromatin. J Comp Neurol 98(2):213–231

    Article  CAS  PubMed  Google Scholar 

  2. Ohno S, Kaplan WD, Kinosita R (1959) Formation of the sex chromatin by a single X-chromosome in liver cells of Rattus norvegicus. Exp Cell Res 18:415–418

    Article  CAS  PubMed  Google Scholar 

  3. • Lyon MF (1961) Gene action in the X-chromosome of the mouse (Mus musculus L.). Nature 190:372–373 This is the first report proposing occurrence of X chromosome inactivation in mammals

    Article  CAS  PubMed  Google Scholar 

  4. • Takagi N, Sasaki M (1975) Preferential inactivation of the paternally derived X chromosome in the extraembryonic membranes of the mouse. Nature 256(5519):640–642 Here, authors provide the first evidence that the paternally inherited X chromosome is inactivated in the extraembryonic tissues. Later, this phenomena lead to the identification of imprinted X-chromosome inactivation

    Article  CAS  PubMed  Google Scholar 

  5. Takagi N, Sugawara O, Sasaki M (1982) Regional and temporal changes in the pattern of X-chromosome replication during the early post-implantation development of the female mouse. Chromosoma 85(2):275–286

    Article  CAS  PubMed  Google Scholar 

  6. Mak W, Nesterova TB, de Napoles M, Appanah R, Yamanaka S, Otte AP et al (2004) Reactivation of the paternal X chromosome in early mouse embryos. Science 303(5658):666–669. doi:10.1126/science.1092674

    Article  CAS  PubMed  Google Scholar 

  7. • Plath K, Fang J, Mlynarczyk-Evans SK, Cao R, Worringer KA, Wang H et al (2003) Role of histone H3 lysine 27 methylation in X inactivation. Science (5616):131–135. doi:10.1126/science.1084274 In this study, the authors provide evidence that histone modification histone 3 lysine 27 trimethylation, which is a histone modification associated with transcriptionally inactive chromatin sites, is a mark that associate with the inactive X chromosome

  8. Silva J, Mak W, Zvetkova I, Appanah R, Nesterova TB, Webster Z et al (2003) Establishment of histone h3 methylation on the inactive X chromosome requires transient recruitment of Eed-Enx1 polycomb group complexes. Dev Cell 4(4):481–495

    Article  CAS  PubMed  Google Scholar 

  9. Csankovszki G, Nagy A, Jaenisch R (2001) Synergism of Xist RNA, DNA methylation, and histone hypoacetylation in maintaining X chromosome inactivation. J Cell Biol 153(4):773–784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. • Sado T, Fenner MH, Tan SS, Tam P, Shioda T, Li E (2000) X inactivation in the mouse embryo deficient for Dnmt1: distinct effect of hypomethylation on imprinted and random X inactivation. Dev Biol 225(2):294–303. doi:10.1006/dbio.2000.9823 This study reports that DNA methyltransferase 1 (Dnmt1 activity is necessary for the stability of random X chromosme inactivation in the embryo proper

    Article  CAS  PubMed  Google Scholar 

  11. Takagi N (1974) Differentiation of X chromosomes in early female mouse embryos. Exp Cell Res 86(1):127–135

    Article  CAS  PubMed  Google Scholar 

  12. Gribnau J, Luikenhuis S, Hochedlinger K, Monkhorst K, Jaenisch R (2005) X chromosome choice occurs independently of asynchronous replication timing. J Cell Biol 168(3):365–373. doi:10.1083/jcb.200405117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Spatz A, Borg C, Feunteun J (2004) X-chromosome genetics and human cancer. Nat Rev Cancer 4(8):617–629. doi:10.1038/nrc1413

    Article  CAS  PubMed  Google Scholar 

  14. Heinonen K, Mahlamaki E, Riikonen P, Meltoranta RL, Rahiala J, Perkkio M (1999) Acquired X-chromosome aneuploidy in children with acute lymphoblastic leukemia. Med Pediatr Oncol 32(5):360–365

    Article  CAS  PubMed  Google Scholar 

  15. Liao DJ, Du QQ, Yu BW, Grignon D, Sarkar FH (2003) Novel perspective: focusing on the X chromosome in reproductive cancers. Cancer Investig 21(4):641–658

    Article  CAS  Google Scholar 

  16. Yildirim E, Kirby JE, Brown DE, Mercier FE, Sadreyev RI, Scadden DT et al (2013) Xist RNA is a potent suppressor of hematologic cancer in mice. Cell 152(4):727–742. doi:10.1016/j.cell.2013.01.034

    Article  CAS  PubMed  Google Scholar 

  17. Rastan S (1983) Non-random X-chromosome inactivation in mouse X-autosome translocation embryos--location of the inactivation centre. J Embryol Exp Morphol 78:1–22

    CAS  PubMed  Google Scholar 

  18. • Lee JT, Strauss WM, Dausman JA, Jaenisch R (1996) A 450 kb transgene displays properties of the mammalian X-inactivation center. Cell 86(1):83–94 Lee and colleagues used a 450-kb transgene flanking the Xist locus and show that its integration into an autosome can provide transcriptional silencing

    Article  CAS  PubMed  Google Scholar 

  19. Heard E, Mongelard F, Arnaud D, Avner P (1999) Xist yeast artificial chromosome transgenes function as X-inactivation centers only in multicopy arrays and not as single copies. Mol Cell Biol 19(4):3156–3166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. • Monkhorst K, Jonkers I, Rentmeester E, Grosveld F, Gribnau J (2008) X inactivation counting and choice is a stochastic process: evidence for involvement of an X-linked activator. Cell 132(3):410–421. doi:10.1016/j.cell.2007.12.036 Gribnau and colleagues identified Rnf12 protein as an activator of Xist

    Article  CAS  PubMed  Google Scholar 

  21. Brown SD (1991) XIST and the mapping of the X chromosome inactivation centre. BioEssays 13(11):607–612. doi:10.1002/bies.950131112

    Article  CAS  PubMed  Google Scholar 

  22. • Penny GD, Kay GF, Sheardown SA, Rastan S, Brockdorff N (1996) Requirement for Xist in X chromosome inactivation. Nature 379(6561):131–137. doi:10.1038/379131a0 Brockdorff and colleagues established Xist knockout embryonic stem cells and provided evidence that Xist is essential for initiation of X chromosome inactivation

    Article  CAS  PubMed  Google Scholar 

  23. Brown CJ, Ballabio A, Rupert JL, Lafreniere RG, Grompe M, Tonlorenzi R et al (1991) A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome. Nature 349(6304):38–44. doi:10.1038/349038a0

    Article  CAS  PubMed  Google Scholar 

  24. Brockdorff N, Ashworth A, Kay GF, Cooper P, Smith S, McCabe VM et al (1991) Conservation of position and exclusive expression of mouse Xist from the inactive X chromosome. Nature 351(6324):329–331. doi:10.1038/351329a0

    Article  CAS  PubMed  Google Scholar 

  25. Borsani G, Tonlorenzi R, Simmler MC, Dandolo L, Arnaud D, Capra V et al (1991) Characterization of a murine gene expressed from the inactive X chromosome. Nature 351(6324):325–329. doi:10.1038/351325a0

    Article  CAS  PubMed  Google Scholar 

  26. • Marahrens Y, Panning B, Dausman J, Strauss W, Jaenisch R. Xist-deficient mice are defective in dosage compensation but not spermatogenesis. Genes Dev. 1997;11(2):156–166. The authors generated a conventional Xist knockout and detected female specific lethality suggesting that Xist expression and subsequent initiation of XCI is essential for female development.

  27. Wutz A, Jaenisch R (2000) A shift from reversible to irreversible X inactivation is triggered during ES cell differentiation. Mol Cell 5(4):695–705

    Article  CAS  PubMed  Google Scholar 

  28. Jiang J, Jing Y, Cost GJ, Chiang JC, Kolpa HJ, Cotton AM et al (2013) Translating dosage compensation to trisomy 21. Nature 500(7462):296–300. doi:10.1038/nature12394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. • Lee JT, Lu N (1999) Targeted mutagenesis of Tsix leads to nonrandom X inactivation. Cell 99(1):47–57 Lee showed that deletion of Tsix lncRNA locus leads to nonrandom (skewed) XCI suggesting an antagonistic role for Tsix in Xist expression

    Article  CAS  PubMed  Google Scholar 

  30. Lee JT, Davidow LS, Warshawsky D (1999) Tsix, a gene antisense to Xist at the X-inactivation centre. Nat Genet 21(4):400–404. doi:10.1038/7734

    Article  CAS  PubMed  Google Scholar 

  31. Sado T, Hoki Y, Sasaki H (2005) Tsix silences Xist through modification of chromatin structure. Dev Cell 9(1):159–165. doi:10.1016/j.devcel.2005.05.015

    Article  CAS  PubMed  Google Scholar 

  32. Sun BK, Deaton AM, Lee JT (2006) A transient heterochromatic state in Xist preempts X inactivation choice without RNA stabilization. Mol Cell 21(5):617–628. doi:10.1016/j.molcel.2006.01.028

    Article  CAS  PubMed  Google Scholar 

  33. Ohhata T, Matsumoto M, Leeb M, Shibata S, Sakai S, Kitagawa K et al (2015) Histone H3 lysine 36 trimethylation is established over the Xist promoter by antisense Tsix transcription and contributes to repressing Xist expression. Mol Cell Biol 35(22):3909–3920. doi:10.1128/MCB.00561-15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zhao J, Sun BK, Erwin JA, Song JJ, Lee JT (2008) Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome. Science 322(5902):750–756. doi:10.1126/science.1163045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Tsai CL, Rowntree RK, Cohen DE, Lee JT (2008) Higher order chromatin structure at the X-inactivation center via looping DNA. Dev Biol 319(2):416–425. doi:10.1016/j.ydbio.2008.04.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Nora EP, Lajoie BR, Schulz EG, Giorgetti L, Okamoto I, Servant N et al (2012) Spatial partitioning of the regulatory landscape of the X-inactivation centre. Nature 485(7398):381–385. doi:10.1038/nature11049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Rowley MJ, Corces VG (2016) The three-dimensional genome: principles and roles of long-distance interactions. Curr Opin Cell Biol 40:8–14. doi:10.1016/j.ceb.2016.01.009

    Article  CAS  PubMed  Google Scholar 

  38. Chureau C, Prissette M, Bourdet A, Barbe V, Cattolico L, Jones L et al (2002) Comparative sequence analysis of the X-inactivation center region in mouse, human, and bovine. Genome Res 12(6):894–908. doi:10.1101/gr.152902

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Chureau C, Chantalat S, Romito A, Galvani A, Duret L, Avner P et al (2011) Ftx is a non-coding RNA which affects Xist expression and chromatin structure within the X-inactivation center region. Hum Mol Genet 20(4):705–718. doi:10.1093/hmg/ddq516

    Article  CAS  PubMed  Google Scholar 

  40. Shin J, Bossenz M, Chung Y, Ma H, Byron M, Taniguchi-Ishigaki N et al (2010) Maternal Rnf12/RLIM is required for imprinted X-chromosome inactivation in mice. Nature 467(7318):977–981. doi:10.1038/nature09457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Jonkers I, Barakat TS, Achame EM, Monkhorst K, Kenter A, Rentmeester E et al (2009) RNF12 is an X-encoded dose-dependent activator of X chromosome inactivation. Cell 139(5):999–1011. doi:10.1016/j.cell.2009.10.034

    Article  CAS  PubMed  Google Scholar 

  42. Lee JT, Lu N, Han Y (1999) Genetic analysis of the mouse X inactivation center defines an 80-kb multifunction domain. Proc Natl Acad Sci U S A 96(7):3836–3841

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Tian D, Sun S, Lee JT (2010) The long noncoding RNA, Jpx, is a molecular switch for X chromosome inactivation. Cell 143(3):390–403. doi:10.1016/j.cell.2010.09.049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Barakat TS, Loos F, van Staveren S, Myronova E, Ghazvini M, Grootegoed JA et al (2014) The trans-activator RNF12 and cis-acting elements effectuate X chromosome inactivation independent of X-pairing. Mol Cell 53(6):965–978. doi:10.1016/j.molcel.2014.02.006

    Article  CAS  PubMed  Google Scholar 

  45. Gontan C, Achame EM, Demmers J, Barakat TS, Rentmeester E, van IW et al (2012) RNF12 initiates X-chromosome inactivation by targeting REX1 for degradation. Nature 485(7398):386–390. doi:10.1038/nature11070

    Article  CAS  PubMed  Google Scholar 

  46. Ghirlando R, Felsenfeld G (2016) CTCF: making the right connections. Genes Dev 30(8):881–891. doi:10.1101/gad.277863.116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Chao W, Huynh KD, Spencer RJ, Davidow LS, Lee JT (2002) CTCF, a candidate trans-acting factor for X-inactivation choice. Science 295(5553):345–347. doi:10.1126/science.1065982

    Article  CAS  PubMed  Google Scholar 

  48. Boumil RM, Ogawa Y, Sun BK, Huynh KD, Lee JT (2006) Differential methylation of Xite and CTCF sites in Tsix mirrors the pattern of X-inactivation choice in mice. Mol Cell Biol 26(6):2109–2117. doi:10.1128/MCB.26.6.2109-2117.2006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Xu N, Donohoe ME, Silva SS, Lee JT (2007) Evidence that homologous X-chromosome pairing requires transcription and Ctcf protein. Nat Genet 39(11):1390–1396. doi:10.1038/ng.2007.5

    Article  CAS  PubMed  Google Scholar 

  50. • Sun S, Del Rosario BC, Szanto A, Ogawa Y, Jeon Y, Lee JT (2013) Jpx RNA activates Xist by evicting CTCF. Cell 153(7):1537–1551. doi:10.1016/j.cell.2013.05.028 The authors report that Jpx lncRNA, which was suggested to be an activator of Xist, does so by titrating CTCF protein from the Xist promoter

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Chaumeil J, Le Baccon P, Wutz A, Heard E (2006) A novel role for Xist RNA in the formation of a repressive nuclear compartment into which genes are recruited when silenced. Genes Dev 20(16):2223–2237. doi:10.1101/gad.380906

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Brockdorff N, Ashworth A, Kay GF, McCabe VM, Norris DP, Cooper PJ et al (1992) The product of the mouse Xist gene is a 15 kb inactive X-specific transcript containing no conserved ORF and located in the nucleus. Cell 71(3):515–526

    Article  CAS  PubMed  Google Scholar 

  53. Brown CJ, Hendrich BD, Rupert JL, Lafreniere RG, Xing Y, Lawrence J et al (1992) The human XIST gene: analysis of a 17 kb inactive X-specific RNA that contains conserved repeats and is highly localized within the nucleus. Cell 71(3):527–542

    Article  CAS  PubMed  Google Scholar 

  54. • Wutz A, Rasmussen TP, Jaenisch R (2002) Chromosomal silencing and localization are mediated by different domains of Xist RNA. Nat Genet 30(2):167–174. doi:10.1038/ng820 Wutz and colleagues used transgenes that span the Xist locus and identified different domains that mediate Xist function. Repeat A was identified as a domain that is necessary for the silencing function of Xist

    Article  CAS  PubMed  Google Scholar 

  55. • Jeon Y, Lee JT (2011) YY1 tethers Xist RNA to the inactive X nucleation center. Cell 146(1):119–133. doi:10.1016/j.cell.2011.06.026 In this paper, YY1 transcription factor was identified as a protein that is essential for nucleation of Xist RNA on Xi

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Sigova AA, Abraham BJ, Ji X, Molinie B, Hannett NM, Guo YE et al (2015) Transcription factor trapping by RNA in gene regulatory elements. Science 350(6263):978–981. doi:10.1126/science.aad3346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Sarma K, Levasseur P, Aristarkhov A, Lee JT (2010) Locked nucleic acids (LNAs) reveal sequence requirements and kinetics of Xist RNA localization to the X chromosome. Proc Natl Acad Sci U S A 107(51):22196–22201. doi:10.1073/pnas.1009785107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Chapman AG, Cotton AM, Kelsey AD, Brown CJ (2014) Differentially methylated CpG island within human XIST mediates alternative P2 transcription and YY1 binding. BMC Genet 15:89. doi:10.1186/s12863-014-0089-4

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Makhlouf M, Ouimette JF, Oldfield A, Navarro P, Neuillet D, Rougeulle C (2014) A prominent and conserved role for YY1 in Xist transcriptional activation. Nat Commun 5:4878. doi:10.1038/ncomms5878

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Affar el B, Gay F, Shi Y, Liu H, Huarte M, Wu S et al (2006) Essential dosage-dependent functions of the transcription factor yin yang 1 in late embryonic development and cell cycle progression. Mol Cell Biol 26(9):3565–3581. doi:10.1128/MCB.26.9.3565-3581.2006

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Sui G, Affar el B, Shi Y, Brignone C, Wall NR, Yin P et al (2004) Yin Yang 1 is a negative regulator of p53. Cell 117(7):859–872. doi:10.1016/j.cell.2004.06.004

    Article  CAS  PubMed  Google Scholar 

  62. Donohoe ME, Zhang X, McGinnis L, Biggers J, Li E, Shi Y (1999) Targeted disruption of mouse Yin Yang 1 transcription factor results in peri-implantation lethality. Mol Cell Biol 19(10):7237–7244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Hoki Y, Kimura N, Kanbayashi M, Amakawa Y, Ohhata T, Sasaki H et al (2009) A proximal conserved repeat in the Xist gene is essential as a genomic element for X-inactivation in mouse. Development 136(1):139–146. doi:10.1242/dev.026427

    Article  CAS  PubMed  Google Scholar 

  64. Pullirsch D, Hartel R, Kishimoto H, Leeb M, Steiner G, Wutz A (2010) The Trithorax group protein Ash2l and Saf-A are recruited to the inactive X chromosome at the onset of stable X inactivation. Development 137(6):935–943. doi:10.1242/dev.035956

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Maenner S, Blaud M, Fouillen L, Savoye A, Marchand V, Dubois A et al (2010) 2-D structure of the a region of Xist RNA and its implication for PRC2 association. PLoS Biol 8(1):e1000276. doi:10.1371/journal.pbio.1000276

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Kanhere A, Viiri K, Araujo CC, Rasaiyaah J, Bouwman RD, Whyte WA et al (2010) Short RNAs are transcribed from repressed polycomb target genes and interact with polycomb repressive complex-2. Mol Cell 38(5):675–688. doi:10.1016/j.molcel.2010.03.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Sarma K, Cifuentes-Rojas C, Ergun A, Del Rosario A, Jeon Y, White F et al (2014) ATRX directs binding of PRC2 to Xist RNA and polycomb targets. Cell 159(4):869–883. doi:10.1016/j.cell.2014.10.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. • Simon MD, Pinter SF, Fang R, Sarma K, Rutenberg-Schoenberg M, Bowman SK et al (2013) High-resolution Xist binding maps reveal two-step spreading during X-chromosome inactivation. Nature 504(7480):465–469. doi:10.1038/nature12719 In this paper, the authors used CHART-Seq technique to determine Xist-DNA interaction sites. Xist binding sites were enriched for Ezh2 and H3K27me3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Pinter SF, Sadreyev RI, Yildirim E, Jeon Y, Ohsumi TK, Borowsky M et al (2012) Spreading of X chromosome inactivation via a hierarchy of defined polycomb stations. Genome Res 22(10):1864–1876. doi:10.1101/gr.133751.111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Heard E, Rougeulle C, Arnaud D, Avner P, Allis CD, Spector DL (2001) Methylation of histone H3 at Lys-9 is an early mark on the X chromosome during X inactivation. Cell 107(6):727–738

    Article  CAS  PubMed  Google Scholar 

  71. Goto Y, Gomez M, Brockdorff N, Feil R (2002) Differential patterns of histone methylation and acetylation distinguish active and repressed alleles at X-linked genes. Cytogenet Genome Res 99(1–4):66–74 doi: 71576

    CAS  PubMed  Google Scholar 

  72. de Napoles M, Mermoud JE, Wakao R, Tang YA, Endoh M, Appanah R et al (2004) Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation. Dev Cell 7(5):663–676. doi:10.1016/j.devcel.2004.10.005

    Article  PubMed  Google Scholar 

  73. Keohane AM, O'Neill LP, Belyaev ND, Lavender JS, Turner BM (1996) X-inactivation and histone H4 acetylation in embryonic stem cells. Dev Biol 180(2):618–630. doi:10.1006/dbio.1996.0333

    Article  CAS  PubMed  Google Scholar 

  74. Fang J, Chen T, Chadwick B, Li E, Zhang Y (2004) Ring1b-mediated H2A ubiquitination associates with inactive X chromosomes and is involved in initiation of X inactivation. J Biol Chem 279(51):52812–52815. doi:10.1074/jbc.C400493200

    Article  CAS  PubMed  Google Scholar 

  75. Csankovszki G, Panning B, Bates B, Pehrson JR, Jaenisch R (1999) Conditional deletion of Xist disrupts histone macroH2A localization but not maintenance of X inactivation. Nat Genet 22(4):323–324. doi:10.1038/11887

    Article  CAS  PubMed  Google Scholar 

  76. Chadwick BP, Willard HF (2002) Cell cycle-dependent localization of macroH2A in chromatin of the inactive X chromosome. J Cell Biol 157(7):1113–1123. doi:10.1083/jcb.200112074

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Hernandez-Munoz I, Lund AH, van der Stoop P, Boutsma E, Muijrers I, Verhoeven E et al (2005) 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 102(21):7635–7640. doi:10.1073/pnas.0408918102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Bickmore WA, van Steensel B (2013) Genome architecture: domain organization of interphase chromosomes. Cell 152(6):1270–1284. doi:10.1016/j.cell.2013.02.001

    Article  CAS  PubMed  Google Scholar 

  79. Akhtar A, Gasser SM (2007) The nuclear envelope and transcriptional control. Nat Rev Genet 8(7):507–517. doi:10.1038/nrg2122

    Article  CAS  PubMed  Google Scholar 

  80. Bourgeois CA, Laquerriere F, Hemon D, Hubert J, Bouteille M (1985) New data on the in-situ position of the inactive X chromosome in the interphase nucleus of human fibroblasts. Hum Genet 69(2):122–129

    Article  CAS  PubMed  Google Scholar 

  81. Belmont AS, Bignone F, Ts'o PO (1986) The relative intranuclear positions of Barr bodies in XXX non-transformed human fibroblasts. Exp Cell Res 165(1):165–179

    Article  CAS  PubMed  Google Scholar 

  82. McHugh CA, Chen CK, Chow A, Surka CF, Tran C, McDonel P et al (2015) The Xist lncRNA interacts directly with SHARP to silence transcription through HDAC3. Nature 521(7551):232–236. doi:10.1038/nature14443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Chen CK, Blanco M, Jackson C, Aznauryan E, Ollikainen N, Surka C et al (2016) Xist recruits the X chromosome to the nuclear lamina to enable chromosome-wide silencing. Science. doi:10.1126/science.aae0047

    Google Scholar 

  84. Chow KH, Factor RE, Ullman KS (2012) The nuclear envelope environment and its cancer connections. Nat Rev Cancer 12(3):196–209. doi:10.1038/nrc3219

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Capell BC, Collins FS (2006) Human laminopathies: nuclei gone genetically awry. Nat Rev Genet. 7(12):940–952. doi:10.1038/nrg1906

    Article  CAS  PubMed  Google Scholar 

  86. Shumaker DK, Dechat T, Kohlmaier A, Adam SA, Bozovsky MR, Erdos MR et al (2006) Mutant nuclear lamin A leads to progressive alterations of epigenetic control in premature aging. Proc Natl Acad Sci U S A 103(23):8703–8708. doi:10.1073/pnas.0602569103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Zhang LF, Huynh KD, Lee JT (2007) Perinucleolar targeting of the inactive X during S phase: evidence for a role in the maintenance of silencing. Cell 129(4):693–706. doi:10.1016/j.cell.2007.03.036

    Article  CAS  PubMed  Google Scholar 

  88. Yang F, Deng X, Ma W, Berletch JB, Rabaia N, Wei G et al (2015) The lncRNA Firre anchors the inactive X chromosome to the nucleolus by binding CTCF and maintains H3K27me3 methylation. Genome Biol 16:52. doi:10.1186/s13059-015-0618-0

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Yang F, Babak T, Shendure J, Disteche CM (2010) Global survey of escape from X inactivation by RNA-sequencing in mouse. Genome Res 20(5):614–622. doi:10.1101/gr.103200.109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Hacisuleyman E, Goff LA, Trapnell C, Williams A, Henao-Mejia J, Sun L et al (2014) Topological organization of multichromosomal regions by the long intergenic noncoding RNA Firre. Nat Struct Mol Biol 21(2):198–206. doi:10.1038/nsmb.2764

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Bhatnagar S, Zhu X, Ou J, Lin L, Chamberlain L, Zhu LJ et al (2014) Genetic and pharmacological reactivation of the mammalian inactive X chromosome. Proc Natl Acad Sci U S A 111(35):12591–12598. doi:10.1073/pnas.1413620111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Minajigi A, Froberg JE, Wei C, Sunwoo H, Kesner B, Colognori D et al (2015) Chromosomes. A comprehensive Xist interactome reveals cohesin repulsion and an RNA-directed chromosome conformation. Science 349(6245). doi:10.1126/science.aab2276

  93. Chu C, Zhang QC, da Rocha ST, Flynn RA, Bharadwaj M, Calabrese JM et al (2015) Systematic discovery of Xist RNA binding proteins. Cell 161(2):404–416. doi:10.1016/j.cell.2015.03.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Gilbert DM (2002) Replication timing and transcriptional control: beyond cause and effect. Curr Opin Cell Biol 14(3):377–383

    Article  CAS  PubMed  Google Scholar 

  95. Rivera-Mulia JC, Gilbert DM (2016) Replication timing and transcriptional control: beyond cause and effect—part III. Curr Opin Cell Biol 40:168–178. doi:10.1016/j.ceb.2016.03.022

    Article  CAS  PubMed  Google Scholar 

  96. Panning B, Dausman J, Jaenisch R (1997) X chromosome inactivation is mediated by Xist RNA stabilization. Cell 90(5):907–916

    Article  CAS  PubMed  Google Scholar 

  97. Janicki SM, Tsukamoto T, Salghetti SE, Tansey WP, Sachidanandam R, Prasanth KV et al (2004) From silencing to gene expression: real-time analysis in single cells. Cell 116(5):683–698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Ng K, Daigle N, Bancaud A, Ohhata T, Humphreys P, Walker R et al (2011) A system for imaging the regulatory noncoding Xist RNA in living mouse embryonic stem cells. Mol Biol Cell 22(14):2634–2645. doi:10.1091/mbc.E11-02-0146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. • Diaz-Perez SV, Ferguson DO, Wang C, Csankovszki G, Wang C, Tsai SC et al (2006) A deletion at the mouse Xist gene exposes trans-effects that alter the heterochromatin of the inactive X chromosome and the replication time and DNA stability of both X chromosomes. Genetics 174(3):1115–1133. doi:10.1534/genetics.105.051375 Marahrens and colleagues deleted Xist in female mouse fibroblasts and show that Xist deletion leads to lengthened replication of the mutant inactive X chromosome and X chromosome aneuploidy. This study suggests a role for Xist in Xi stability

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Brown CJ, Willard HF (1994) The human X-inactivation centre is not required for maintenance of X-chromosome inactivation. Nature 368(6467):154–156. doi:10.1038/368154a0

    Article  CAS  PubMed  Google Scholar 

  101. Rack KA, Chelly J, Gibbons RJ, Rider S, Benjamin D, Lafreniere RG et al (1994) Absence of the XIST gene from late-replicating isodicentric X chromosomes in leukaemia. Hum Mol Genet 3(7):1053–1059

    Article  CAS  PubMed  Google Scholar 

  102. Orkin SH, Zon LI (2008) Hematopoiesis: an evolving paradigm for stem cell biology. Cell 132(4):631–644. doi:10.1016/j.cell.2008.01.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Tefferi A, Vainchenker W (2011) Myeloproliferative neoplasms: molecular pathophysiology, essential clinical understanding, and treatment strategies. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 29(5):573–582. doi:10.1200/JCO.2010.29.8711

    Article  CAS  Google Scholar 

  104. Patnaik MM, Tefferi A (2016) Cytogenetic and molecular abnormalities in chronic myelomonocytic leukemia. Blood Cancer Journal 6:e393. doi:10.1038/bcj.2016.5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Takahashi E, Nakamura S (2013) Histiocytic sarcoma : an updated literature review based on the 2008 WHO classification. Journal of Clinical and Experimental Hematopathology: JCEH 53(1):1–8

    Article  PubMed  Google Scholar 

  106. Tefferi A (2011) Primary myelofibrosis: 2012 update on diagnosis, risk stratification, and management. Am J Hematol 86(12):1017–1026. doi:10.1002/ajh.22210

    Article  PubMed  Google Scholar 

  107. Wang PJ, Page DC, McCarrey JR (2005) Differential expression of sex-linked and autosomal germ-cell-specific genes during spermatogenesis in the mouse. Hum Mol Genet 14(19):2911–2918. doi:10.1093/hmg/ddi322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Ropers HH, Hamel BC (2005) X-linked mental retardation. Nat Rev Genet. 6(1):46–57. doi:10.1038/nrg1501

    Article  CAS  PubMed  Google Scholar 

  109. Zechner U, Wilda M, Kehrer-Sawatzki H, Vogel W, Fundele R, Hameister H (2001) A high density of X-linked genes for general cognitive ability: a run-away process shaping human evolution? Trends Genet 17(12):697–701

    Article  CAS  PubMed  Google Scholar 

  110. Nguyen DK, Disteche CM (2006) High expression of the mammalian X chromosome in brain. Brain Res 1126(1):46–49. doi:10.1016/j.brainres.2006.08.053

    Article  CAS  PubMed  Google Scholar 

  111. Xu J, Disteche CM (2006) Sex differences in brain expression of X- and Y-linked genes. Brain Res 1126(1):50–55. doi:10.1016/j.brainres.2006.08.049

    Article  CAS  PubMed  Google Scholar 

  112. Davoli T, Xu AW, Mengwasser KE, Sack LM, Yoon JC, Park PJ et al (2013) Cumulative haploinsufficiency and triplosensitivity drive aneuploidy patterns and shape the cancer genome. Cell 155(4):948–962. doi:10.1016/j.cell.2013.10.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Fratta E, Coral S, Covre A, Parisi G, Colizzi F, Danielli R et al (2011) The biology of cancer testis antigens: putative function, regulation and therapeutic potential. Mol Oncol 5(2):164–182. doi:10.1016/j.molonc.2011.02.001

    Article  CAS  PubMed  Google Scholar 

  114. Yang L, Kirby JE, Sunwoo H, Lee JT (2016) Female mice lacking Xist RNA show partial dosage compensation and survive to term. Genes Dev 30(15):1747–1760. doi:10.1101/gad.281162.116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Fearon ER, Winkelstein JA, Civin CI, Pardoll DM, Vogelstein B (1987) Carrier detection in X-linked agammaglobulinemia by analysis of X-chromosome inactivation. N Engl J Med 316(8):427–431. doi:10.1056/NEJM198702193160802

    Article  CAS  PubMed  Google Scholar 

  116. Winkelstein JA, Fearon E (1990) Carrier detection of the X-linked primary immunodeficiency diseases using X-chromosome inactivation analysis. J Allergy Clin Immunol 85(6):1090–1097

    Article  CAS  PubMed  Google Scholar 

  117. Amir RE, Zoghbi HY (2000) Rett syndrome: methyl-CpG-binding protein 2 mutations and phenotype-genotype correlations. Am J Med Genet 97(2):147–152

    Article  CAS  PubMed  Google Scholar 

  118. Barr ML, Moore KL (1957) Chromosomes, sex chromatin, and cancer. Proc Can Cancer Conf 2:3–16

    CAS  PubMed  Google Scholar 

  119. Kawakami T, Zhang C, Taniguchi T, Kim CJ, Okada Y, Sugihara H et al (2004) Characterization of loss-of-inactive X in Klinefelter syndrome and female-derived cancer cells. Oncogene 23(36):6163–6169. doi:10.1038/sj.onc.1207808

    Article  CAS  PubMed  Google Scholar 

  120. Sirchia SM, Ramoscelli L, Grati FR, Barbera F, Coradini D, Rossella F et al (2005) Loss of the inactive X chromosome and replication of the active X in BRCA1-defective and wild-type breast cancer cells. Cancer Res 65(6):2139–2146. doi:10.1158/0008-5472.CAN-04-3465

    Article  CAS  PubMed  Google Scholar 

  121. Richardson AL, Wang ZC, De Nicolo A, Lu X, Brown M, Miron A et al (2006) X chromosomal abnormalities in basal-like human breast cancer. Cancer Cell 9(2):121–132. doi:10.1016/j.ccr.2006.01.013

    Article  CAS  PubMed  Google Scholar 

  122. Benoit MH, Hudson TJ, Maire G, Squire JA, Arcand SL, Provencher D et al (2007) Global analysis of chromosome X gene expression in primary cultures of normal ovarian surface epithelial cells and epithelial ovarian cancer cell lines. Int J Oncol 30(1):5–17

    PubMed  Google Scholar 

  123. Jager N, Schlesner M, Jones DT, Raffel S, Mallm JP, Junge KM et al (2013) Hypermutation of the inactive X chromosome is a frequent event in cancer. Cell 155(3):567–581. doi:10.1016/j.cell.2013.09.042

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Soria G, Polo SE, Almouzni G (2012) Prime, repair, restore: the active role of chromatin in the DNA damage response. Mol Cell 46(6):722–734. doi:10.1016/j.molcel.2012.06.002

    Article  CAS  PubMed  Google Scholar 

  125. Jazaeri AA, Yee CJ, Sotiriou C, Brantley KR, Boyd J, Liu ET (2002) Gene expression profiles of BRCA1-linked, BRCA2-linked, and sporadic ovarian cancers. J Natl Cancer Inst 94(13):990–1000

    Article  CAS  PubMed  Google Scholar 

  126. Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A et al (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A 100(14):8418–8423. doi:10.1073/pnas.0932692100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Hultborn R, Hanson C, Kopf I, Verbiene I, Warnhammar E, Weimarck A (1997) Prevalence of Klinefelter's syndrome in male breast cancer patients. Anticancer Res 17(6D):4293–4297

    CAS  PubMed  Google Scholar 

  128. Schoemaker MJ, Swerdlow AJ, Higgins CD, Wright AF, Jacobs PA, Group UKCC (2008) Cancer incidence in women with Turner syndrome in Great Britain: a national cohort study. Lancet Oncol 9(3):239–246. doi:10.1016/S1470-2045(08)70033-0

    Article  PubMed  Google Scholar 

  129. Chaligne R, Popova T, Mendoza-Parra MA, Saleem MA, Gentien D, Ban K et al (2015) The inactive X chromosome is epigenetically unstable and transcriptionally labile in breast cancer. Genome Res 25(4):488–503. doi:10.1101/gr.185926.114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Suva ML, Riggi N, Bernstein BE (2013) Epigenetic reprogramming in cancer. Science 339(6127):1567–1570. doi:10.1126/science.1230184

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank all the members of the Yildirim lab for helpful discussions. This work was support by Leukemia Research Foundation Award (E.Y), Whitehead Research Fellowship (E.Y.), and Duke University Medical School Department of Cell Biology Startup Funds (E.Y.).

Author information

Authors and Affiliations

  1. Department of Cell Biology, Duke University Medical Center, Durham, NC, 27710, USA

    Tianqi Yang & Eda Yildirim

  2. Department of Pharmacology, Duke University Medical Center, Durham, NC, 27710, USA

    Tianqi Yang

  3. Duke Cancer Institute, Duke University Medical Center, Durham, NC, 27710, USA

    Tianqi Yang & Eda Yildirim

Authors
  1. Tianqi Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eda Yildirim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eda Yildirim.

Ethics declarations

Conflict of Interest

Tianqi Yang and Eda Yildirim declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on RNA in Pathobiology

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, T., Yildirim, E. Epigenetic and LncRNA-Mediated Regulation of X Chromosome Inactivation and Its Impact on Pathogenesis. Curr Pathobiol Rep 5, 1–12 (2017). https://doi.org/10.1007/s40139-017-0120-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40139-017-0120-3

Keywords

Search

Navigation