Abstract
The phenomenon of X chromosome inactivation in female mammals is well characterised and remains the archetypal example of dosage compensation via monoallelic expression. The temporal series of events that culminates in inactive X-specific gene silencing by DNA methylation has revealed a ‘patchwork’ of gene inactivation along the chromosome, with approximately 15% of genes escaping. Such genes are therefore potentially subject to sex-specific imbalance between males and females. Aside from XIST, the non-coding RNA on the X chromosome destined to be inactivated, very little is known about the extent of loci that may be selectively silenced on the active X chromosome (Xa). Using longitudinal array-based DNA methylation profiling of two human tissues, we have identified specific and widespread active X-specific DNA methylation showing stability over time and across tissues of disparate origin. Our panel of X-chromosome loci subject to methylation on Xa reflects a potentially novel mechanism for controlling female-specific X inactivation and sex-specific dimorphisms in humans. Further work is needed to investigate these phenomena.
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References
Wutz A : Gene silencing in X-chromosome inactivation: advances in understanding facultative heterochromatin formation. Nat Rev Genet 2011; 12: 542–553.
Payer B, Lee JT, Namekawa SH : X-inactivation and X-reactivation: epigenetic hallmarks of mammalian reproduction and pluripotent stem cells. Hum Genet 2011; 130: 265–280.
Takagi N, Sasaki M : Preferential inactivation of the paternally derived X chromosome in the extraembryonic membranes of the mouse. Nature 1975; 256: 640–642.
Morey C, Avner P : The demoiselle of X-inactivation: 50 years old and as trendy and mesmerising as ever. PLoS Genet 2011; 7: e1002212.
Brown CJ, Lafreniere RG, Powers VE et al: Localization of the X inactivation centre on the human X chromosome in Xq13. Nature 1991; 349: 82–84.
Brown CJ, Ballabio A, Rupert JL et al: A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome. Nature 1991; 349: 38–44.
Brockdorff N : Chromosome silencing mechanisms in X-chromosome inactivation: unknown unknowns. Development 2011; 138: 5057–5065.
Brockdorff N, Ashworth A, Kay GF et al: Conservation of position and exclusive expression of mouse Xist from the inactive X chromosome. Nature 1991; 351: 329–331.
Jeon Y, Sarma K, Lee JT : New and Xisting regulatory mechanisms of X chromosome inactivation. Curr Opin Genet Dev 2012; 22: 62–71.
Sado T, Hoki Y, Sasaki H : Tsix silences Xist through modification of chromatin structure. Dev Cell 2005; 9: 159–165.
Carrel L, Willard HF : X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 2005; 434: 400–404.
Johnston CM, Lovell FL, Leongamornlert DA, Stranger BE, Dermitzakis ET, Ross MT : Large-scale population study of human cell lines indicates that dosage compensation is virtually complete. PLoS Genet 2008; 4: e9.
Yasukochi Y, Maruyama O, Mahajan MC et al: X chromosome-wide analyses of genomic DNA methylation states and gene expression in male and female neutrophils. Proc Natl Acad Sci USA 2010; 107: 3704–3709.
Sharp AJ, Stathaki E, Migliavacca E et al: DNA methylation profiles of human active and inactive X chromosomes. Genome Res 2011; 21: 1592–1600.
Cruickshank MN, Oshlack A, Theda C et al: Analysis of epigenetic changes in survivors of preterm birth 1 reveals the effect of gestational age and evidence for a long term legacy. Genome Med 2013; 5: 96.
Martino D, Loke YJ, Gordon L et al: Longitudinal, genome-scale analysis of DNA methylation in twins from birth to 18 months of age reveals rapid epigenetic change in early life and pair-specific effects of discordance. Genome Biol 2013; 14: R42.
Roberts G, Cheong J, Opie G et al: Growth of extremely preterm survivors from birth to 18 years of age compared with term controls. Pediatrics 2013; 131: e439–e445.
Saffery R, Morley R, Carlin JB et al: Cohort profile: the peri/post-natal epigenetic twins study. Int J Epidemiol 2012; 41: 55–61.
Ollikainen M, Smith KR, Joo EJ et al: DNA methylation analysis of multiple tissues from newborn twins reveals both genetic and intrauterine components to variation in the human neonatal epigenome. Hum Mol Genet 2010; 19: 4176–4188.
Gentleman RC, Carey VJ, Bates DM et al: Bioconductor: open software development for computational biology and bioinformatics. Genome Biol 2004; 5: R80.
Maksimovic J, Gordon L, Oshlack A : SWAN: Subset quantile Within-Array Normalization for Illumina Infinium Human Methylation450 BeadChips. Genome Biol 2012; 13: R44.
Smyth GK : Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 2004; 3: Article3.
Davis S, Meltzer PS : GEOquery: a bridge between the Gene Expression Omnibus (GEO) and BioConductor. Bioinformatics 2007; 23: 1846–1847.
Grossmann V, Tiacci E, Holmes AB et al: Whole-exome sequencing identifies somatic mutations of BCOR in acute myeloid leukemia with normal karyotype. Blood 2011; 118: 6153–6163.
Pugh TJ, Weeraratne SD, Archer TC et al: Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations. Nature 2012; 488: 106–110.
Gianfrancesco F, Sanges R, Esposito T et al: Differential divergence of three human pseudoautosomal genes and their mouse homologs: implications for sex chromosome evolution. Genome Res 2001; 11: 2095–2100.
Charchar FJ, Svartman M, El-Mogharbel N et al: Complex events in the evolution of the human pseudoautosomal region 2 (PAR2). Genome Res 2003; 13: 281–286.
Pierron G, Tirode F, Lucchesi C et al: A new subtype of bone sarcoma defined by BCOR-CCNB3 gene fusion. Nat Genet 2012; 44: 461–466.
Yamamoto Y, Tsuzuki S, Tsuzuki M, Handa K, Inaguma Y, Emi N : BCOR as a novel fusion partner of retinoic acid receptor alpha in a t(X;17)(p11;q12) variant of acute promyelocytic leukemia. Blood 2010; 116: 4274–4283.
Ndlovu MN, Denis H, Fuks F : Exposing the DNA methylome iceberg. Trends Biochem Sci 2011; 36: 381–387.
Jones PA : Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet 2012; 13: 484–492.
Adams D, Altucci L, Antonarakis SE et al: BLUEPRINT to decode the epigenetic signature written in blood. Nat Biotechnol 2012; 30: 224–226.
Reddy TE, Gertz J, Pauli F et al: Effects of sequence variation on differential allelic transcription factor occupancy and gene expression. Genome Res 2012; 22: 860–869.
Sheffield NC, Thurman RE, Song L et al: Patterns of regulatory activity across diverse human cell types predict tissue identity, transcription factor binding, and long-range interactions. Genome Res 2013; 23: 777–788.
Acknowledgements
This study is supported by the National Health and Medical Research Council (Project Grant 491246 to LWD; 437015 and 607358 to JMC and RS; Centre for Clinical Research Excellence 546519 to LWD), by the MCRI and the Victorian Government’s Operational Infrastructure Support Program.
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Joo, J., Novakovic, B., Cruickshank, M. et al. Human active X-specific DNA methylation events showing stability across time and tissues. Eur J Hum Genet 22, 1376–1381 (2014). https://doi.org/10.1038/ejhg.2014.34
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DOI: https://doi.org/10.1038/ejhg.2014.34
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