Abstract
Adults with 45,X monosomy (Turner syndrome) reflect a surviving minority since more than 99% of fetuses with 45,X monosomy die in utero. In adulthood 45,X monosomy is associated with increased morbidity and mortality, although strikingly heterogeneous with some individuals left untouched while others suffer from cardiovascular disease, autoimmune disease and infertility. The present study investigates the leukocyte DNAmethylation profile by using the 450K-Illumina Infinium assay and the leukocyte RNA-expression profile in 45,X monosomy compared with karyotypically normal female and male controls. We present results illustrating that genome wide X-chromosome RNA-expression profile, autosomal DNA-methylation profile, and the X-chromosome methylation profile clearly distinguish Turner syndrome from controls. Our results reveal genome wide hypomethylation with most differentially methylated positions showing a medium level of methylation. Contrary to previous studies, applying a single loci specific analysis at well-defined DNA loci, our results indicate that the hypomethylation extend to repetitive elements. We describe novel candidate genes that could be involved in comorbidity in TS and explain congenital urinary malformations (PRKX), premature ovarian failure (KDM6A), and aortic aneurysm formation (ZFYVE9 and TIMP1).
Highlights
45,X monosomy (Turner syndrome) is the only chromosome haploinsufficiency compatible with life
Evidence suggests that sex chromosomes regulate gene expression throughout the genome with an influence on 3% of autosomal genes[11]
This study illustrates that 45,X monosomy is associated with genome wide DNA hypomethylation in both cis and trans, and to a lesser extent areas of hypermethylation
Summary
45,X monosomy (Turner syndrome) is the only chromosome haploinsufficiency compatible with life. Identifying causal genes of Turner syndrome comorbidity is complicated since Turner syndrome is non-heritable, making familiar-genetic analysis non-applicable, and no good animal model is available Both functional disomy of constitutively mono-allelic expressed genes in TS individuals with mosaic ring X-chromosomes (chrX)[5], as well as functional monosomy of constitutively bi-allelic expressed genes[6,7,8,9] have been linked to TS and morbidity, but results are equivocal[10]. Low resolution DNA-methylation studies bring evidence of an altered methylome in 45,X fibroblast cell lines[16,17,18] as well as in peripheral blood mononuclear cells[19,20,21] These studies suggest an altered global gene expression partly due to changes www.nature.com/scientificreports/. We provide evidence of global changes of the TS methylation landscape, accompanied by subtle gene expression differences with special emphasis on genes escaping X-inactivation (escape genes) and the pseudo-autosomal region
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