DNA methylation signature in peripheral blood reveals distinct characteristics of human X chromosome numerical aberrations
Open accessAbstract
BACKGROUND: Abnormal sex chromosome numbers in humans are observed in Turner (45,X) and Klinefelter (47,XXY) syndromes. Both syndromes are associated with several clinical phenotypes, whose molecular mechanisms are obscure, and show a range of inter-individual penetrance. In order to understand the effect of abnormal numbers of X chromosome on the methylome and its correlation to the variable clinical phenotype, we performed a genome-wide methylation analysis using MeDIP and Illumina's Infinium assay on individuals with four karyotypes: 45,X, 46,XY, 46,XX, and 47,XXY. RESULTS: DNA methylation changes were widespread on all autosomal chromosomes in 45,X and in 47,XXY individuals, with Turner individuals presenting five times more affected loci. Differentially methylated CpGs, in most cases, have intermediate methylation levels and tend to occur outside CpG islands, especially in individuals with Turner syndrome. The X inactivation process appears to be less effective in Klinefelter syndrome as methylation on the X was decreased compared to normal female samples. In a large number of individuals, we verified several loci by pyrosequencing and observed only weak inter-loci correlations between the verified regions. This suggests a certain stochastic/random contribution to the methylation changes at each locus. Interestingly, methylation patterns on some PAR2 loci differ between male and Turner syndrome individuals and between female and Klinefelter syndrome individuals, which possibly contributed to this distinguished and unique autosomal methylation patterns in Turner and Klinefelter syndrome individuals. CONCLUSIONS: The presented data clearly show that gain or loss of an X chromosome results in different epigenetic effects, which are not necessary opposite.
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There is evidence of a unique and tissue-specific genome-wide methylation and transcription landscape in TS extending to both the X chromosome and the autosomes.
“There is evidence of a unique and tissue-specific genome-wide methylation and transcription landscape in TS extending to both the X chromosome and the autosomes.103-109”
From Clinical practice guidelines for the care of girls and women with Turner syndrome. (2024) · cites this paper as [108]
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REVIGO summarizes and visualizes long lists of gene ontology terms
Supek, F., Bošnjak, M., Škunca, N., & Šmuc, T. (2011) · PLoS ONE · doi:10.1371/journal.pone.0021800 · Cited by 6,264 · see citing works
limma: Linear Models for Microarray Data
Smyth, G. K. (2005) · Statistics for Biology and Health · doi:10.1007/0-387-29362-0_23 · Cited by 5,796 · see citing works
Bioinformatics and Computational Biology Solutions Using R and Bioconductor
Gentleman, R. C., Carey, V. J., Huber, W. K., Irizarry, R. A., & Dudoit, S. (2005) · Statistics in the health sciences · doi:10.1007/0-387-29362-0 · Cited by 3,470 · see citing works
GOrilla: a tool for discovery and visualization of enriched GO terms in ranked gene lists
Eden, E., Navon, R., Steinfeld, I., Lipson, D., & Yakhini, Z. (2009) · BMC Bioinformatics · doi:10.1186/1471-2105-10-48 · Cited by 3,356 · see citing works
Epigenetic memory in induced pluripotent stem cells
Kim, K., Doi, A., Wen, B., Ng, K., Zhao, R., Cahan, P., Kim, J., Aryee, M., Ji, H., Ehrlich, L., et al. (2010) · Nature · doi:10.1038/nature09342 · Cited by 2,429 · see citing works
Weber, M., Hellmann, I., Stadler, M. B., Ramos, L., Pääbo, S., Rebhan, M., & Schübeler, D. (2007) · Nature Genetics · doi:10.1038/ng1990 · Cited by 2,267 · see citing works
Du, P., Zhang, X., Huang, C.-C., Jafari, N., Kibbe, W. A., Hou, L., & Lin, S. M. (2010) · BMC Bioinformatics · doi:10.1186/1471-2105-11-587 · Cited by 2,136 · see citing works
X-inactivation profile reveals extensive variability in X-linked gene expression in females
Carrel, L., & Willard, H. F. (2005) · Nature · doi:10.1038/nature03479 · Cited by 2,097 · see citing works
lumi : a pipeline for processing Illumina microarray
Du, P., Kibbe, W. A., & Lin, S. M. (2008) · Bioinformatics · doi:10.1093/bioinformatics/btn224 · Cited by 2,028 · see citing works
Polo, J. M., Liu, S. X., Figueroa, M. E., Kulalert, W., Eminli, S., Tan, K. Y., Apostolou, E., Stadtfeld, M., Li, Y., Shioda, T., et al. (2010) · Nature Biotechnology · doi:10.1038/nbt.1667 · Cited by 1,194 · see citing works
Aging of blood can be tracked by DNA methylation changes at just three CpG sites
Weidner, C. I., Lin, Q., Koch, C., Eisele, L., Beier, F., Ziegler, P., Bauerschlag, D., Jöckel, K., Erbel, R., Mühleisen, T., et al. (2014) · Genome Biology · doi:10.1186/gb-2014-15-2-r24 · Cited by 849 · see citing works
Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domainsPreprint
Rakyan, V. K., Down, T. A., Maslau, S., Andrew, T., Yang, T.-P., Beyan, H., Whittaker, P., McCann, O. T., Finer, S., Valdes, A. M., et al. (2010) · Genome Research · doi:10.1101/gr.103101.109 · Cited by 750 · see citing works
Bell, J., Tsai, P.-C., Yang, T.-P., Pidsley, R., Nisbet, J. P., Glass, D., Mangino, M., Zhai, G., Zhang, F., Valdes, A., et al. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002629 · Cited by 722 · see citing works
Miki, K., Qu, W., Goulding, E. H., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0407708101 · Cited by 614 · see citing works
Klinefelter Syndrome—A Clinical Update
Groth, K. A., Skakkebaek, A. H., Høst, C., Gravholt, C. H., & Bojesen, A. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-2382 · Cited by 497 · see citing works
Mouse Sycp1 functions in synaptonemal complex assembly, meiotic recombination, and XY body formationPreprint
de Vries, F. A. T., de Boer, E., van den Bosch, M., et al. (2005) · Genes & Development · doi:10.1101/gad.329705 · Cited by 459 · see citing works
(2002) · PubMed · Cited by 440 · see citing works
Klinefelter syndrome and other sex chromosomal aneuploidies
Visootsak, J., & Graham, J. M. (2006) · Orphanet Journal of Rare Diseases · doi:10.1186/1750-1172-1-42 · Cited by 369 · see citing works
The Human Pseudoautosomal Region (PAR): Origin, Function and Future
Mangs, A. H., & Morris, B. J. (2007) · Current Genomics · doi:10.2174/138920207780368141 · Cited by 289 · see citing works
Cognitive and neurological aspects of sex chromosome aneuploidies
Hong, D. S., & Reiss, A. L. (2014) · The Lancet Neurology · doi:10.1016/s1474-4422(13)70302-8 · Cited by 209 · see citing works
Li, X., & Schimenti, J. C. (2007) · PLoS Genetics · doi:10.1371/journal.pgen.0030130 · Cited by 202 · see citing works
Frost, R. J., Hamra, F. K., Richardson, J. A., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1007158107 · Cited by 200 · see citing works
Fujihara, Y., Satouh, Y., Inoue, N., et al. (2012) · Development · doi:10.1242/dev.081778 · Cited by 181 · see citing works
Autoimmune thyroid syndrome in women with Turner's syndrome—the association with karyotype
Elsheikh, M., Wass, J. A. H., & Conway, G. S. (2001) · Clinical Endocrinology · doi:10.1046/j.1365-2265.2001.01296.x · Cited by 171 · see citing works
An Epigenetic Memory of Pregnancy in the Mouse Mammary Gland
dos Santos, C. O., Dolzhenko, E., Hodges, E. C., Smith, A. D., & Hannon, G. J. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.04.015 · Cited by 145 · see citing works
Ear and hearing in relation to genotype and growth in Turner syndrome
Barrenäs, M., Landin‐Wilhelmsen, K., & Hanson, C. (2000) · Hearing Research · doi:10.1016/s0378-5955(00)00040-x · Cited by 137 · see citing works
Renal malformations in patients with Turner syndrome: imaging in 141 patients
Lippe, B., Geffner, M. E., Dietrich, R. B., Boechat, M. I., & Kangarloo, H. (1988) · PEDIATRICS · doi:10.1542/peds.82.6.852 · Cited by 122 · see citing works
Birdwell, C. E., Queen, K. J., Kilgore, P. C. S. R., Rollyson, P. A., Trutschl, M., Cvek, U., & Scott, R. S. (2014) · Journal of Virology · doi:10.1128/jvi.00972-14 · Cited by 108 · see citing works
The role of hypogonadism in Klinefelter Syndrome
Bojesen, A., Høst, C., Skakkebaek, A. H., & Groth, K. A. (2014) · Asian Journal of Andrology · doi:10.4103/1008-682x.122201 · Cited by 105 · see citing works
Gene Expression Patterns in Relation to the Clinical Phenotype in Klinefelter Syndrome
Zitzmann, M., Bongers, R., Werler, S., Bogdanova, N., Wistuba, J., Kliesch, S., Gromoll, J., & Tüttelmann, F. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-2780 · Cited by 104 · see citing works
The genetics of sex chromosomes: evolution and implications for hybrid incompatibility
Johnson, N., & Lachance, J. (2012) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2012.06748.x · Cited by 100 · see citing works
A synaptobrevin–like gene in the Xq28 pseudoautosomal region undergoes X inactivation
D'Esposito, M., Ciccodicola, A., Gianfrancesco, F., et al. (1996) · Nature Genetics · doi:10.1038/ng0696-227 · Cited by 92 · see citing works
Chen, Y.-A., Choufani, S., Ferreira, J. C., Grafodatskaya, D., Butcher, D. T., & Weksberg, R. (2011) · Genomics · doi:10.1016/j.ygeno.2010.12.004 · Cited by 90 · see citing works
Autoimmunity and Turner's syndrome
Lleò, A., Moroni, L., Caliari, L., & Invernizzi, P. (2011) · Autoimmunity Reviews · doi:10.1016/j.autrev.2011.11.015 · Cited by 86 · see citing works
Frequency of renal malformations in Turner syndrome: analysis of 82 Turkish children
Bilge, I., Kayserili, H., Emre, S., Nayir, A., Sirin, A., Tukel, T., Bas, F., Kilic, G., Basaran, S., Gunoz, H., et al. (2000) · Pediatric Nephrology · doi:10.1007/s004670000315 · Cited by 77 · see citing works
Epigenetics and autoimmune diseases: the X chromosome-nucleolus nexus
Brooks, W. H., & Renaudineau, Y. (2015) · Frontiers in Genetics · doi:10.3389/fgene.2015.00022 · Cited by 72 · see citing works
D’Aurora, M., Ferlin, A., Nicola, M. D., Garolla, A., Toni, L. D., Franchi, S., Palka, G., Foresta, C., Stuppia, L., & Gatta, V. (2015) · BMC Genomics · doi:10.1186/s12864-015-1356-0 · Cited by 63 · see citing works
Hewitt, J. K., Jayasinghe, Y., Amor, D. J., Gillam, L. H., Warne, G. L., Grover, S. R., & Zacharin, M. (2013) · Clinical Endocrinology · doi:10.1111/cen.12288 · Cited by 59 · see citing works
Influence of the X-Chromosome on Neuroanatomy: Evidence from Turner and Klinefelter Syndromes
Hong, D. S., Hoeft, F., Marzelli, M., Lepage, J., Roeltgen, D. P., ROSS, J. L., & Reiss, A. L. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.2790-13.2014 · Cited by 57 · see citing works
Hearing loss in Turner syndrome
Morimoto, N., Tanaka, T., Taiji, H., Horikawa, R., Naiki, Y., Morimoto, Y., & Kawashiro, N. (2006) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2006.06.071 · Cited by 54 · see citing works
Park, E.-S., & Tilly, J. L. (2014) · Molecular Human Reproduction · doi:10.1093/molehr/gau071 · Cited by 53 · see citing works
Amniotic fluid RNA gene expression profiling provides insights into the phenotype of Turner syndrome
Massingham, L. J., Johnson, K. L., Scholl, T. M., Slonim, D. K., Wick, H. C., & Bianchi, D. W. (2014) · Human Genetics · doi:10.1007/s00439-014-1448-y · Cited by 52 · see citing works
Bonis, M. L. D., Cerase, A., Matarazzo, M. R., et al. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl027 · Cited by 51 · see citing works
Rajpathak, S. N., Vellarikkal, S. K., Patowary, A., Scaria, V., Sivasubbu, S., & Deobagkar, D. D. (2014) · PLoS ONE · doi:10.1371/journal.pone.0100076 · Cited by 51 · see citing works
Epigenomic and transcriptomic signatures of a Klinefelter syndrome (47,XXY) karyotype in the brain
Viana, J. F., Pidsley, R., Troakes, C., Spiers, H., Wong, C. C. Y., Al‐Sarraj, S., Craig, I., Schalkwyk, L. C., & Mill, J. S. (2014) · Epigenetics · doi:10.4161/epi.27806 · Cited by 50 · see citing works
Friemel, C., Ammerpohl, O., Gutwein, J., Schmutzler, A. G., Caliebe, A., Kautza, M., von Otte, S., Siebert, R., & Bens, S. (2014) · Fertility and Sterility · doi:10.1016/j.fertnstert.2013.12.054 · Cited by 49 · see citing works
Matarazzo, M. R. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.25.3191 · Cited by 48 · see citing works
Ros, C., Alobid, I., Balasch, J., Mullol, J., & Castelo-Branco, C. (2013) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2013.01.011 · Cited by 47 · see citing works
Paillisson, A., Levasseur, A., Gouret, P., Callebaut, I., Bontoux, M., Pontarotti, P., & Monget, P. (2006) · Genomics · doi:10.1016/j.ygeno.2006.09.002 · Cited by 42 · see citing works
Singer, H., Walier, M., Nüsgen, N., Meesters, C., Schreiner, F., Woelfle, J., Fimmers, R., Wienker, T. F., Kalscheuer, V. M., Becker, T., et al. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr456 · Cited by 31 · see citing works
Self-citationHuang, J., Zhang, L., Deng, H., Chang, L., Liu, Q., & Liu, P. (2015) · Molecular Reproduction and Development · doi:10.1002/mrd.22438 · Cited by 30 · see citing works
Severe XIST hypomethylation clearly distinguishes (SRY+) 46,XX-maleness from Klinefelter syndrome
Poplinski, A., Wieacker, P. F., Kliesch, S., et al. (2009) · European Journal of Endocrinology · doi:10.1530/eje-09-0768 · Cited by 26 · see citing works
Sarkardeh, H., Totonchi, M., Asadpour, O., et al. (2014) · Journal of Assisted Reproduction and Genetics · doi:10.1007/s10815-014-0240-1 · Cited by 19 · see citing works
Renal malformations in children with Turner's syndrome.
Chang, P., Tsau, Y., Tsai, W., Tsai, W. S., Hou, J. W., Hsiao, P. H., & Lee, J. S. (2000) · PubMed · Cited by 19 · see citing works
Novel methylation specific real-time PCR test for the diagnosis of Klinefelter syndrome
Mehta, A., Mielnik, A., Schlegel, P., et al. (2014) · Asian Journal of Andrology · doi:10.4103/1008-682x.125914 · Cited by 10 · see citing works
Fetal diagnosis of monosomy X (Turner syndrome) with methylation‐specific PCR
Pena, S. D. J., & Sturzeneker, R. (2003) · Prenatal Diagnosis · doi:10.1002/pd.675 · Cited by 3 · see citing works
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Gravholt, C. H., Andersen, N. H., Christin-Maitre, S., Davis, S. M., Duijnhouwer, A., Gawlik, A., Maciel-Guerra, A. T., Gutmark-Little, I., Fleischer, K., Hong, D., et al. (2024) · European Journal of Endocrinology · doi:10.1093/ejendo/lvae050 · Cited by 224 · see citing works
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Maschietto, M., Bastos, L. C., Tahira, A. C., Bastos, E. P., Euclydes, V. L. V., Brentani, A., Fink, G., de Baumont, A., Felipe-Silva, A., Francisco, R. P. V., et al. (2017) · Scientific Reports · doi:10.1038/srep44547 · Cited by 78 · see citing works
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Viuff, M., Skakkebæk, A., Johannsen, E. B., Chang, S., Pedersen, S. B., Lauritsen, K. M., Pedersen, M. G. B., Trolle, C., Just, J., & Gravholt, C. H. (2023) · Genome Medicine · doi:10.1186/s13073-023-01169-4 · Cited by 34 · see citing works
- Authors
- Sharma, A., Jamil, M. A., Nuesgen, N., Schreiner, F., Priebe, L., Hoffmann, P., Herns, S., Nöthen, M. M., Fröhlich, H., Oldenburg, J., Woelfle, J., & El-Maarri, O.
- Affiliations
- University of Bonn (DE)
- ORCID
- Venue
- Clinical Epigenetics
- Published
- 2015-07-28
- Volume
- 7
- Issue
- 1
- Pages
- 76-76
- ISSN
- 1868-7075 (ISSN-L)
- 1868-7083
- PMC
- PMC4517491
- OpenAlex
- W2099864996
- Cited by
- 81
- References
- 56
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 4 · 2023: 10 · 2022: 8 · 2021: 13 · 2020: 15 · 2019: 9 · 2018: 6 · 2017: 5 · 2016: 2
- FWCI
- 2.96
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Clinical Epigenetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Keywords
- DNA methylation, Turner syndrome, Klinefelter syndrome, sex chromosome aneuploidy, X chromosome inactivation, differentially methylated CpGs, peripheral blood, penetrance
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