X chromosome regulation: diverse patterns in development, tissues and disease (original) (raw)

• Livernois, A. M., Graves, J. A. & Waters, P. D. The origin and evolution of vertebrate sex chromosomes and dosage compensation. Hered. (Edinb.) 108, 50–58 (2012).
  Article CAS Google Scholar
• Disteche, C. M. Dosage compensation of the sex chromosomes. Annu. Rev. Genet. 46, 537–560 (2012).
  Article CAS PubMed Central PubMed Google Scholar
• Bachtrog, D. Y-chromosome evolution: emerging insights into processes of Y-chromosome degeneration. Nature Rev. Genet. 14, 113–124 (2013).
  Article CAS PubMed Google Scholar
• Gurbich, T. A. & Bachtrog, D. Gene content evolution on the X chromosome. Curr. Opin. Genet. Dev. 18, 493–498 (2008).
  Article CAS PubMed Central PubMed Google Scholar
• Wang, P. J., McCarrey, J. R., Yang, F. & Page, D. C. An abundance of X-linked genes expressed in spermatogonia. Nature Genet. 27, 422–426 (2001).
  Article PubMed CAS Google Scholar
• Mueller, J. L. et al. The mouse X chromosome is enriched for multicopy testis genes showing postmeiotic expression. Nature Genet. 40, 794–799 (2008).
  Article CAS PubMed Google Scholar
• Rice, W. R. Sexually antagonistic genes: experimental evidence. Science 256, 1436–1439 (1992).
  Article CAS PubMed Google Scholar
• Adra, C. N., Ellis, N. A. & McBurney, M. W. The family of mouse phosphoglycerate kinase genes and pseudogenes. Somat. Cell. Mol. Genet. 14, 69–81 (1988).
  Article CAS PubMed Google Scholar
• Ro, S., Park, C., Sanders, K. M., McCarrey, J. R. & Yan, W. Cloning and expression profiling of testis-expressed microRNAs. Dev. Biol. 311, 592–602 (2007).
  Article CAS PubMed Central PubMed Google Scholar
• Ross, M. T. et al. The DNA sequence of the human X chromosome. Nature 434, 325–337 (2005).
  Article CAS PubMed Central PubMed Google Scholar
• Mueller, J. L. et al. Independent specialization of the human and mouse X chromosomes for the male germ line. Nature Genet. 45, 1083–1087 (2013). This paper shows that many ampliconic X-linked genes are expressed predominantly in testicular germ cells and were independently acquired since the divergence between humans and mice.
  Article CAS PubMed Google Scholar
• Rugarli, E. I. et al. Different chromosomal localization of the Clcn4 gene in Mus spretus and C57BL/6J mice. Nature Genet. 10, 466–471 (1995).
  Article CAS PubMed Google Scholar
• Bellott, D. W. et al. Convergent evolution of chicken Z and human X chromosomes by expansion and gene acquisition. Nature 466, 612–616 (2010). This study comprehensively compares the chicken Z and human X chromosomes, and shows that they share common features such as acquisition and amplification of testis-specific genes.
  Article CAS PubMed Central PubMed Google Scholar
• Zhang, Y. E., Vibranovski, M. D., Landback, P., Marais, G. A. & Long, M. Chromosomal redistribution of male-biased genes in mammalian evolution with two bursts of gene gain on the X chromosome. PLoS Biol. 8, e1000494 (2010).
  Article PubMed Central PubMed CAS Google Scholar
• Khil, P. P., Smirnova, N. A., Romanienko, P. J. & Camerini-Otero, R. D. The mouse X chromosome is enriched for sex-biased genes not subject to selection by meiotic sex chromosome inactivation. Nature Genet. 36, 642–646 (2004).
  Article CAS PubMed Google Scholar
• Ohhata, T. & Wutz, A. Reactivation of the inactive X chromosome in development and reprogramming. Cell. Mol. Life Sci. 70, 2443–2461 (2012).
  Article PubMed Central PubMed CAS Google Scholar
• Payer, B. et al. Tsix RNA and the germline factor, PRDM14, link X reactivation and stem cell reprogramming. Mol. Cell 52, 805–818 (2013).
  Article CAS PubMed Central PubMed Google Scholar
• Zechner, U. et al. A high density of X-linked genes for general cognitive ability: a run-away process shaping human evolution? Trends Genet. 17, 697–701 (2001).
  Article CAS PubMed Google Scholar
• Marshall Graves, J. A. The rise and fall of SRY. Trends Genet. 18, 259–264 (2002).
  Article CAS PubMed Google Scholar
• Nguyen, D. K. & Disteche, C. M. High expression of the mammalian X chromosome in brain. Brain Res. 1126, 46–49 (2006).
  Article CAS PubMed Google Scholar
• Deng, X. et al. Evidence for compensatory upregulation of expressed X-linked genes in mammals, Caenorhabditis elegans and Drosophila melanogaster. Nature Genet. 43, 1179–1185 (2011). This paper confirms that there is dosage compensation of gene expression between the X chromosome and autosomes in both sexes of mammals, nematodes and fruitflies, and proposes the need to take into consideration the skewed gene content and regulation of the X chromosome in the study of dosage compensation.
  Article CAS PubMed Google Scholar
• Skuse, D. H. X-linked genes and mental functioning. Hum. Mol. Genet. 14 (suppl. 1), R27–R32 (2005).
  Article CAS PubMed Google Scholar
• Ropers, H. H. Genetics of early onset cognitive impairment. Annu. Rev. Genom. Hum. Genet. 11, 161–187 (2010).
  Article CAS Google Scholar
• Nguyen, D. K. & Disteche, C. M. Dosage compensation of the active X chromosome in mammals. Nature Genet. 38, 47–53 (2006).
  Article CAS PubMed Google Scholar
• Lin, H. et al. Relative overexpression of X-linked genes in mouse embryonic stem cells is consistent with Ohno's hypothesis. Nature Genet. 43, 1169–1170 (2011).
  Article CAS PubMed Google Scholar
• Yildirim, E., Sadreyev, R. I., Pinter, S. F. & Lee, J. T. X-chromosome hyperactivation in mammals via nonlinear relationships between chromatin states and transcription. Nature Struct. Mol. Biol. 19, 56–61 (2011).
  Article CAS Google Scholar
• Deng, X. et al. Mammalian X upregulation is associated with enhanced transcription initiation, RNA half-life, and MOF-mediated H4K16 acetylation. Dev. Cell 25, 55–68 (2013). This study shows that subsets of mammalian X-linked genes rely on different X upregulation mechanisms.
  Article CAS PubMed Central PubMed Google Scholar
• Yin, S. et al. Evidence that the nonsense-mediated mRNA decay pathway participates in X chromosome dosage compensation in mammals. Biochem. Biophys. Res. Commun. 383, 378–382 (2009).
  Article CAS PubMed Google Scholar
• Julien, P. et al. Mechanisms and evolutionary patterns of mammalian and avian dosage compensation. PLoS Biol. 10, e1001328 (2012).
  Article CAS PubMed Central PubMed Google Scholar
• Pessia, E., Makino, T., Bailly-Bechet, M., McLysaght, A. & Marais, G. A. Mammalian X chromosome inactivation evolved as a dosage-compensation mechanism for dosage-sensitive genes on the X chromosome. Proc. Natl Acad. Sci. USA 109, 5346–5351 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Zhang, Y. et al. Expression in aneuploid Drosophila S2 cells. PLoS Biol. 8, e1000320 (2010).
  Article PubMed Central PubMed CAS Google Scholar
• Prestel, M., Feller, C. & Becker, P. B. Dosage compensation and the global re-balancing of aneuploid genomes. Genome Biol. 11, 216 (2010).
  Article PubMed Central PubMed CAS Google Scholar
• Birchler, J. A., Pal-Bhadra, M. & Bhadra, U. Dosage dependent gene regulation and the compensation of the X chromosome in Drosophila males. Genetica 117, 179–190 (2003).
  Article CAS PubMed Google Scholar
• Escamilla-Del-Arenal, M., da Rocha, S. T. & Heard, E. Evolutionary diversity and developmental regulation of X-chromosome inactivation. Hum. Genet. 130, 307–327 (2011).
  Article CAS PubMed Central PubMed Google Scholar
• Arnold, A. P. The end of gonad-centric sex determination in mammals. Trends Genet. 28, 55–61 (2011).
  Article PubMed Central PubMed CAS Google Scholar
• Migeon, B. R. Females are Mosaic: X Inactivation and Sex Differences in Disease (Oxford Univ. Press, 2014).
  Google Scholar
• Lessing, D. & Lee, J. T. X chromosome inactivation and epigenetic responses to cellular reprogramming. Annu. Rev. Genom. Hum. Genet. 14, 85–110 (2013).
  Article CAS Google Scholar
• Morey, C. & Avner, P. The demoiselle of X-inactivation: 50 years old and as trendy and mesmerising as ever. PLoS Genet. 7, e1002212 (2011).
  Article CAS PubMed Central PubMed Google Scholar
• Pollex, T. & Heard, E. Recent advances in X-chromosome inactivation research. Curr. Opin. Cell Biol. 24, 825–832 (2013).
  Article CAS Google Scholar
• Sado, T., Wang, Z., Sasaki, H. & Li, E. Regulation of imprinted X-chromosome inactivation in mice by Tsix. Development 128, 1275–1286 (2001).
  Article CAS PubMed Google Scholar
• Lee, J. T. Disruption of imprinted X inactivation by parent-of-origin effects at Tsix. Cell 103, 17–27 (2000).
  Article CAS PubMed Google Scholar
• Mak, W. et al. Reactivation of the paternal X chromosome in early mouse embryos. Science 303, 666–669 (2004).
  Article CAS PubMed Google Scholar
• Schulz, E. G. et al. The two active X chromosomes in female ESCs block exit from the pluripotent state by modulating the ESC signaling network. Cell Stem Cell 14, 203–216 (2014).
  Article CAS PubMed Google Scholar
• Engreitz, J. M. et al. The Xist lncRNA exploits three-dimensional genome architecture to spread across the X chromosome. Science 341, 1237973 (2013).
  Article PubMed Central PubMed CAS Google Scholar
• Nozawa, R. S. et al. Human inactive X chromosome is compacted through a PRC2-independent SMCHD1–HBiX1 pathway. Nature Struct. Mol. Biol. 20, 566–573 (2013).
  Article CAS Google Scholar
• Gendrel, A. V. et al. Epigenetic functions of Smchd1 repress gene clusters on the inactive X chromosome and on autosomes. Mol. Cell. Biol. 33, 3150–3165 (2013).
  Article CAS PubMed Central PubMed Google Scholar
• Gendrel, A. V. et al. Smchd1-dependent and -independent pathways determine developmental dynamics of CpG island methylation on the inactive X chromosome. Dev. Cell 23, 265–279 (2012). This study shows that X-linked genes are silenced at different times during development.
  Article CAS PubMed Central PubMed Google Scholar
• Okamoto, I. et al. Eutherian mammals use diverse strategies to initiate X-chromosome inactivation during development. Nature 472, 370–374 (2011). This paper is the first study of XCI in rabbit and human early embryos, and shows that these species have different strategies to initiate XCI compared with mice.
  Article CAS PubMed Google Scholar
• van den Berg, I. M. et al. X chromosome inactivation is initiated in human preimplantation embryos. Am. J. Hum. Genet. 84, 771–779 (2009).
  Article CAS PubMed Central PubMed Google Scholar
• Wang, X., Miller, D. C., Clark, A. G. & Antczak, D. F. Random X inactivation in the mule and horse placenta. Genome Res. 22, 1855–1863 (2012).
  Article CAS PubMed Central PubMed Google Scholar
• Mugford, J. W., Yee, D. & Magnuson, T. Failure of extra-embryonic progenitor maintenance in the absence of dosage compensation. Development 139, 2130–2138 (2012).
  Article CAS PubMed Central PubMed Google Scholar
• Russell, L. B. Genetics of mammalian sex chromosomes. Science 133, 1795–1803 (1961).
  Article CAS PubMed Google Scholar
• Thomas, N. S. & Hassold, T. J. Aberrant recombination and the origin of Klinefelter syndrome. Hum. Reprod. Update 9, 309–317 (2003).
  Article CAS PubMed Google Scholar
• Kirchhof, N. et al. Expression pattern of Oct-4 in preimplantation embryos of different species. Biol. Reprod. 63, 1698–1705 (2000).
  Article CAS PubMed Google Scholar
• Monkhorst, K., Jonkers, I., Rentmeester, E., Grosveld, F. & Gribnau, J. X inactivation counting and choice is a stochastic process: evidence for involvement of an X-linked activator. Cell 132, 410–421 (2008).
  Article CAS PubMed Google Scholar
• Chang, S. C. & Brown, C. J. Identification of regulatory elements flanking human XIST reveals species differences. BMC Mol. Biol. 11, 20 (2010).
  Article PubMed Central PubMed CAS Google Scholar
• Vallot, C. et al. XACT, a long noncoding transcript coating the active X chromosome in human pluripotent cells. Nature Genet. 45, 239–241 (2013).
  Article CAS PubMed Google Scholar
• Graves, J. A. Sex chromosome specialization and degeneration in mammals. Cell 124, 901–914 (2006).
  Article PubMed CAS Google Scholar
• 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).
  Article CAS PubMed Central PubMed Google Scholar
• Grant, J. et al. Rsx is a metatherian RNA with _Xist_-like properties in X-chromosome inactivation. Nature 487, 254–258 (2012).
  Article CAS PubMed Central PubMed Google Scholar
• Wang, X., Douglas, K. C., Vandeberg, J. L., Clark, A. G. & Samollow, P. B. Chromosome-wide profiling of X-chromosome inactivation and epigenetic states in fetal brain and placenta of the opossum, Monodelphis domestica. Genome Res. 24, 70–83 (2014).
  Article CAS PubMed Central PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Wu, H. et al. Cellular resolution maps of X chromosome inactivation: implications for neural development, function, and disease. Neuron 81, 103–119 (2014). This study obtains comprehensive maps of XCI in vivo by differentially labelling each X chromosome with fluorescent markers and evaluates escape from XCI in the brain by cell sorting.
  Article CAS PubMed Central PubMed Google Scholar
• Berletch, J. B., Yang, F., Xu, J., Carrel, L. & Disteche, C. M. Genes that escape from X inactivation. Hum. Genet. 130, 237–245 (2011).
  Article PubMed Central PubMed Google Scholar
• Johnston, C. M. et al. Large-scale population study of human cell lines indicates that dosage compensation is virtually complete. PLoS Genet. 4, e9 (2008).
  Article PubMed Central PubMed CAS Google Scholar
• Jegalian, K. & Page, D. C. A proposed path by which genes common to mammalian X and Y chromosomes evolve to become X inactivated. Nature 394, 776–780 (1998).
  Article CAS PubMed Google Scholar
• Lee, J. T. & Bartolomei, M. S. X-inactivation, imprinting, and long noncoding RNAs in health and disease. Cell 152, 1308–1323 (2013).
  Article CAS PubMed Google Scholar
• Calabrese, J. M. et al. Site-specific silencing of regulatory elements as a mechanism of X inactivation. Cell 151, 951–963 (2012).
  Article CAS PubMed Central PubMed Google Scholar
• Yang, F., Babak, T., Shendure, J. & Disteche, C. M. Global survey of escape from X inactivation by RNA-sequencing in mouse. Genome Res. 20, 614–622 (2010). This is the first report of a comprehensive XCI profile of the mouse X chromosome based on an allele-specific RNA sequencing analysis, which shows fewer escape genes in mice than in humans.
  Article CAS PubMed Central PubMed Google Scholar
• Changolkar, L. N. et al. Genome-wide distribution of macroH2A1 histone variants in mouse liver chromatin. Mol. Cell. Biol. 30, 5473–5483 (2010).
  Article CAS PubMed Central PubMed Google Scholar
• Splinter, E. et al. The inactive X chromosome adopts a unique three-dimensional conformation that is dependent on Xist RNA. Genes Dev. 25, 1371–1383 (2011). This paper reports allele-specific chromosome conformation capture-on-chip assays to produce high-resolution topology maps of the active and inactive X chromosomes, and to show that escape genes are engaged in long-range contacts with each other.
  Article CAS PubMed Central PubMed Google Scholar
• 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). This paper shows that the chromatin insulator CCCTC-binding factor (CTCF) is bound to transition regions between domains of inactivation and escape, which suggests a role in protection of these domains from encroachment of neighbouring domains.
  Article CAS PubMed Google Scholar
• Horvath, L. M., Li, N. & Carrel, L. Deletion of an X-inactivation boundary disrupts adjacent gene silencing. PLoS Genet. 9, e1003952 (2013). This study shows that deletion of boundary elements between inactivated and escape chromatin leads to the spreading of escape and thus inappropriate reactivation of genes that are normally silenced.
  Article PubMed Central PubMed CAS Google Scholar
• Reinius, B. et al. Female-biased expression of long non- coding RNAs in domains that escape X-inactivation in mouse. BMC Genomics 11, 614 (2010).
  Article PubMed Central PubMed CAS Google Scholar
• Lopes, A. M., Arnold-Croop, S. E., Amorim, A. & Carrel, L. Clustered transcripts that escape X inactivation at mouse XqD. Mamm. Genome 22, 572–582 (2011).
  Article CAS PubMed Google Scholar
• Carrel, L. & Willard, H. F. X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 434, 400–404 (2005). This is the first comprehensive report of XCI and escape from XCI in humans that was obtained in interspecific fibroblast-based systems; it shows that a remarkable degree of expression heterogeneity exists among females.
  Article CAS PubMed Google Scholar
• Lister, R. et al. Global epigenomic reconfiguration during mammalian brain development. Science 341, 1237905 (2013).
  Article PubMed Central PubMed CAS Google Scholar
• Cotton, A. M. et al. Chromosome-wide DNA methylation analysis predicts human tissue-specific X inactivation. Hum. Genet. 130, 187–201 (2011). This study shows tissue-specific differences in escape from XCI on the basis of analyses of DNA methylation patterns in humans.
  Article CAS PubMed Central PubMed Google Scholar
• Anderson, C. L. & Brown, C. J. Variability of X chromosome inactivation: effect on levels of TIMP1 RNA and role of DNA methylation. Hum. Genet. 110, 271–278 (2002).
  Article CAS PubMed Google Scholar
• Lingenfelter, P. A. et al. Escape from X inactivation of Smcx is preceded by silencing during mouse development. Nature Genet. 18, 212–213 (1998).
  Article CAS PubMed Google Scholar
• Patrat, C. et al. Dynamic changes in paternal X-chromosome activity during imprinted X-chromosome inactivation in mice. Proc. Natl Acad. Sci. USA 106, 5198–5203 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Moreira de Mello, J. C. et al. Random X inactivation and extensive mosaicism in human placenta revealed by analysis of allele-specific gene expression along the X chromosome. PLoS ONE 5, e10947 (2010).
  Article PubMed Central PubMed CAS Google Scholar
• Trabzuni, D. et al. Widespread sex differences in gene expression and splicing in the adult human brain. Nature Commun. 4, 2771 (2013).
  Article CAS Google Scholar
• Morgan, C. P. & Bale, T. L. Sex differences in microRNA regulation of gene expression: no smoke, just miRs. Biol. Sex. Differ. 3, 22 (2012).
  Article CAS PubMed Central PubMed Google Scholar
• Kobayashi, S. et al. The X-linked imprinted gene family Fthl17 shows predominantly female expression following the two-cell stage in mouse embryos. Nucleic Acids Res. 38, 3672–3681 (2010).
  Article CAS PubMed Central PubMed Google Scholar
• Bermejo-Alvarez, P., Rizos, D., Lonergan, P. & Gutierrez-Adan, A. Transcriptional sexual dimorphism during preimplantation embryo development and its consequences for developmental competence and adult health and disease. Reproduction 141, 563–570 (2011).
  Article CAS PubMed Google Scholar
• Berletch, J. B., Deng, X., Nguyen, D. K. & Disteche, C. M. Female bias in Rhox6 and 9 regulation by the histone demethylase KDM6A. PLoS Genet. 9, e1003489 (2013).
  Article CAS PubMed Central PubMed Google Scholar
• Bermejo-Alvarez, P., Rizos, D., Rath, D., Lonergan, P. & Gutierrez-Adan, A. Sex determines the expression level of one third of the actively expressed genes in bovine blastocysts. Proc. Natl Acad. Sci. USA 107, 3394–3399 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Arnold, A. P. Mouse models for evaluating sex chromosome effects that cause sex differences in non-gonadal tissues. J. Neuroendocrinol. 21, 377–386 (2009). This paper describes the 4CG mouse model to evaluate effects of the sex chromosome complement separately from hormonal effects.
  Article CAS PubMed Central PubMed Google Scholar
• Caeiro, X. E., Mir, F. R., Vivas, L. M., Carrer, H. F. & Cambiasso, M. J. Sex chromosome complement contributes to sex differences in bradycardic baroreflex response. Hypertension 58, 505–511 (2011).
  Article CAS PubMed Google Scholar
• Chen, X. et al. The number of X chromosomes causes sex differences in adiposity in mice. PLoS Genet. 8, e1002709 (2012).
  Article CAS PubMed Central PubMed Google Scholar
• Wijchers, P. J. et al. Sexual dimorphism in mammalian autosomal gene regulation is determined not only by Sry but by sex chromosome complement as well. Dev. Cell 19, 477–484 (2010). This paper shows genome-wide effects on X-linked and autosomal gene expression that originate from differences in the number of X and Y chromosomes in mice.
  Article CAS PubMed Google Scholar
• Eicher, E. M. et al. The mouse Y* chromosome involves a complex rearrangement, including interstitial positioning of the pseudoautosomal region. Cytogenet. Cell Genet. 57, 221–230 (1991).
  Article CAS PubMed Google Scholar
• Wolstenholme, J. T., Rissman, E. F. & Bekiranov, S. Sexual differentiation in the developing mouse brain: contributions of sex chromosome genes. Genes Brain Behav. 12, 166–180 (2013).
  Article CAS PubMed Central PubMed Google Scholar
• Lopes, A. M. et al. Transcriptional changes in response to X chromosome dosage in the mouse: implications for X inactivation and the molecular basis of Turner Syndrome. BMC Genomics 11, 82 (2010).
  Article PubMed Central PubMed CAS Google Scholar
• Xu, J., Deng, X. & Disteche, C. M. Sex-specific expression of the X-linked histone demethylase gene Jarid1c in brain. PLoS ONE 3, e2553 (2008).
  Article PubMed Central PubMed CAS Google Scholar
• Grafodatskaya, D. et al. Multilocus loss of DNA methylation in individuals with mutations in the histone H3 lysine 4 demethylase KDM5C. BMC Med. Genom. 6, 1 (2013).
  Article CAS Google Scholar
• Shpargel, K. B., Sengoku, T., Yokoyama, S. & Magnuson, T. UTX and UTY demonstrate histone demethylase-independent function in mouse embryonic development. PLoS Genet. 8, e1002964 (2012).
  Article CAS PubMed Central PubMed Google Scholar
• Leppig, K. A. & Disteche, C. M. Ring X and other structural X chromosome abnormalities: X inactivation and phenotype. Semin. Reprod. Med. 19, 147–157 (2001).
  Article CAS PubMed Google Scholar
• Spatz, A., Borg, C. & Feunteun, J. X-chromosome genetics and human cancer. Nature Rev. Cancer 4, 617–629 (2004).
  Article CAS Google Scholar
• Gentilini, D. et al. Age-dependent skewing of X chromosome inactivation appears delayed in centenarians' offspring. Is there a role for allelic imbalance in healthy aging and longevity? Aging Cell 11, 277–283 (2012).
  Article CAS PubMed Google Scholar
• Clerc, P. & Avner, P. Random X-chromosome inactivation: skewing lessons for mice and men. Curr. Opin. Genet. Dev. 16, 246–253 (2006).
  Article CAS PubMed Google Scholar
• Invernizzi, P., Pasini, S. & Podda, M. X chromosome in autoimmune diseases. Expert Rev. Clin. Immunol. 4, 591–597 (2008).
  Article CAS PubMed Google Scholar
• Busque, L. et al. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nature Genet. 44, 1179–1181 (2012).
  Article CAS PubMed Google Scholar
• Medema, R. H. & Burgering, B. M. The X factor: skewing X inactivation towards cancer. Cell 129, 1253–1254 (2007).
  Article CAS PubMed Google Scholar
• van Haaften, G. et al. Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nature Genet. 41, 521–523 (2009).
  Article CAS PubMed Google Scholar
• Jones, D. T. et al. Dissecting the genomic complexity underlying medulloblastoma. Nature 488, 100–105 (2012).
  Article CAS PubMed Central PubMed Google Scholar
• Grasso, C. S. et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature 487, 239–243 (2012).
  Article CAS PubMed Central PubMed Google Scholar
• Miyake, N. et al. KDM6A point mutations cause Kabuki syndrome. Hum. Mutat. 34, 108–110 (2012).
  Article PubMed CAS Google Scholar
• Lederer, D. et al. Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome. Am. J. Hum. Genet. 90, 119–124 (2012).
  Article CAS PubMed Central PubMed Google Scholar
• Lindgren, A. M. et al. Haploinsufficiency of KDM6A is associated with severe psychomotor retardation, global growth restriction, seizures and cleft palate. Hum. Genet. 132, 537–552 (2013).
  Article CAS PubMed Central PubMed Google Scholar
• Jensen, L. R. et al. A distinctive gene expression fingerprint in mentally retarded male patients reflects disease-causing defects in the histone demethylase KDM5C. Pathog. 3, 2 (2010).
  Google Scholar
• Simensen, R. J. et al. Short-term memory deficits in carrier females with KDM5C mutations. Genet. Couns. 23, 31–40 (2013).
  Google Scholar
• Heard, E. & Turner, J. Function of the sex chromosomes in mammalian fertility. Cold Spring Harb. Perspect. Biol. 3, a002675 (2011).
  Article PubMed Central PubMed CAS Google Scholar
• Sybert, V. P. & McCauley, E. Turner's syndrome. N. Engl. J. Med. 351, 1227–1238 (2004).
  Article CAS PubMed Google Scholar
• Zinn, A. R., Page, D. C. & Fisher, E. M. Turner syndrome: the case of the missing sex chromosome. Trends Genet. 9, 90–93 (1993).
  Article CAS PubMed Google Scholar
• Hassold, T., Pettay, D., Robinson, A. & Uchida, I. Molecular studies of parental origin and mosaicism in 45,X conceptuses. Hum. Genet. 89, 647–652 (1992).
  Article CAS PubMed Google Scholar
• Werler, S., Poplinski, A., Gromoll, J. & Wistuba, J. Expression of selected genes escaping from X inactivation in the 41, XX(Y)* mouse model for Klinefelter's syndrome. Acta Paediatr. 100, 885–891 (2011).
  Article CAS PubMed Google Scholar
• Gropman, A. & Samango-Sprouse, C. A. Neurocognitive variance and neurological underpinnings of the X and Y chromosomal variations. Am. J. Med. Genet. C Semin. Med. Genet. 163, 35–43 (2013).
  Article Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Yildirim, E. et al. Xist RNA is a potent suppressor of hematologic cancer in mice. Cell 152, 727–742 (2013). This study shows that loss of Xist in the blood compartment of female mice causes an aggressive form of cancer, which suggests that abnormal X reactivation and consequent genome-wide changes can lead to disease.
  Article CAS PubMed Google Scholar
• Leong, H. S. et al. Epigenetic regulator Smchd1 functions as a tumor suppressor. Cancer Res. 73, 1591–1599 (2012).
  Article PubMed CAS Google Scholar
• 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).
  Article CAS PubMed Central PubMed Google Scholar
• Wareham, K. A., Lyon, M. F., Glenister, P. H. & Williams, E. D. Age related reactivation of an X-linked gene. Nature 327, 725–727 (1987).
  Article CAS PubMed Google Scholar
• Lu, Q. et al. Demethylation of CD40LG on the inactive X in T cells from women with lupus. J. Immunol. 179, 6352–6358 (2007).
  Article CAS PubMed Google Scholar
• Zandman-Goddard, G. & Peeva, E. Connective tissue diseases. Unravelling aetiology in male SLE — the X chromosome dose effect. Nature Rev. Rheumatol 8, 310–312 (2012).
  Article Google Scholar
• Deng, X. & Disteche, C. M. Genomic responses to abnormal gene dosage: the X chromosome improved on a common strategy. PLoS Biol. 8, e1000318 (2010).
  Article PubMed Central PubMed CAS Google Scholar