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      Exploratory analysis of age and sex dependent DNA methylation patterns on the X-chromosome in whole blood samples


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          Large numbers of autosomal sites are found differentially methylated in the aging genome. Due to analytical difficulties in dealing with sex differences in X-chromosome content and X-inactivation (XCI) in females, this has not been explored for the X chromosome.


          Using data from middle age to elderly individuals (age 55+ years) from two Danish cohorts of monozygotic twins and the Scottish Lothian Birth Cohort 1921, we conducted an X-chromosome-wide analysis of age-associated DNA methylation patterns with consideration of stably inferred XCI status.


          Through analysing and comparing sex-specific X-linked DNA methylation changes over age late in life, we identified 123, 293 and 55 CpG sites significant (FDR < 0.05) only in males, only in females and in both sexes of Danish twins. All findings were significantly replicated in the two Danish twin cohorts. CpG sites escaping XCI are predominantly de-methylated with increasing age across cohorts. In contrast, CpGs highly methylated in both sexes are methylated even further with increasing age. Among the replicated sites in Danish samples, 16 (13%), 24 (8.2%) and 3 (5.5%) CpGs were further validated in LBC1921 (FDR < 0.05).


          The X-chromosome of whole blood leukocytes displays age- and sex-dependent DNA methylation patterns in relation to XCI across cohorts.

          Electronic supplementary material

          The online version of this article (10.1186/s13073-020-00736-3) contains supplementary material, which is available to authorized users.

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          Most cited references37

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          Gene action in the X-chromosome of the mouse (Mus musculus L.).

          MARY LYON (1961)
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            DNA methylation age of blood predicts all-cause mortality in later life

            Background DNA methylation levels change with age. Recent studies have identified biomarkers of chronological age based on DNA methylation levels. It is not yet known whether DNA methylation age captures aspects of biological age. Results Here we test whether differences between people’s chronological ages and estimated ages, DNA methylation age, predict all-cause mortality in later life. The difference between DNA methylation age and chronological age (Δage) was calculated in four longitudinal cohorts of older people. Meta-analysis of proportional hazards models from the four cohorts was used to determine the association between Δage and mortality. A 5-year higher Δage is associated with a 21% higher mortality risk, adjusting for age and sex. After further adjustments for childhood IQ, education, social class, hypertension, diabetes, cardiovascular disease, and APOE e4 status, there is a 16% increased mortality risk for those with a 5-year higher Δage. A pedigree-based heritability analysis of Δage was conducted in a separate cohort. The heritability of Δage was 0.43. Conclusions DNA methylation-derived measures of accelerated aging are heritable traits that predict mortality independently of health status, lifestyle factors, and known genetic factors. Electronic supplementary material The online version of this article (doi:10.1186/s13059-015-0584-6) contains supplementary material, which is available to authorized users.
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              Gene body methylation can alter gene expression and is a therapeutic target in cancer.

              DNA methylation in promoters is well known to silence genes and is the presumed therapeutic target of methylation inhibitors. Gene body methylation is positively correlated with expression, yet its function is unknown. We show that 5-aza-2'-deoxycytidine treatment not only reactivates genes but decreases the overexpression of genes, many of which are involved in metabolic processes regulated by c-MYC. Downregulation is caused by DNA demethylation of the gene bodies and restoration of high levels of expression requires remethylation by DNMT3B. Gene body methylation may, therefore, be an unexpected therapeutic target for DNA methylation inhibitors, resulting in the normalization of gene overexpression induced during carcinogenesis. Our results provide direct evidence for a causal relationship between gene body methylation and transcription. Copyright © 2014 Elsevier Inc. All rights reserved.

                Author and article information

                Genome Med
                Genome Med
                Genome Medicine
                BioMed Central (London )
                28 April 2020
                28 April 2020
                : 12
                : 39
                [1 ]GRID grid.10825.3e, ISNI 0000 0001 0728 0170, Epidemiology and Biostatistics, Department of Public Health, Faculty of Health Science, , University of Southern Denmark, ; J. B. Winsløws Vej 9B, DK-5000 Odense C, Denmark
                [2 ]GRID grid.10825.3e, ISNI 0000 0001 0728 0170, Unit of Human Genetics, Department of Clinical Research, , University of Southern Denmark, ; Odense, Denmark
                [3 ]GRID grid.6936.a, ISNI 0000000123222966, Chair of Experimental Bioinformatics, TUM School of Life Sciences Weihenstephan, , Technical University of Munich, ; Freising, Germany
                [4 ]GRID grid.4305.2, ISNI 0000 0004 1936 7988, Department of Psychology, , University of Edinburgh, ; Edinburgh, Scotland UK
                [5 ]GRID grid.4305.2, ISNI 0000 0004 1936 7988, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, , University of Edinburgh, ; Edinburgh, Scotland, UK
                [6 ]GRID grid.4305.2, ISNI 0000 0004 1936 7988, Lothian Birth Cohorts, , University of Edinburgh, ; Edinburgh, Scotland, UK
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                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                : 14 October 2019
                : 7 April 2020
                Funded by: FundRef http://dx.doi.org/10.13039/100008397, Velux Fonden;
                Award ID: 000121540
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                © The Author(s) 2020

                Molecular medicine
                x-chromosome,dna methylation,x-inactivation,whole blood,aging,twins
                Molecular medicine
                x-chromosome, dna methylation, x-inactivation, whole blood, aging, twins


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