Integrated functional genomic analyses of Klinefelter and Turner syndromes reveal global network effects of altered X chromosome dosage

Abstract

In both Turner syndrome (TS) and Klinefelter syndrome (KS) copy number aberrations of the X chromosome lead to various developmental symptoms. We report a comparative analysis of TS vs. KS regarding differences at the genomic network level measured in primary samples by analyzing gene expression, DNA methylation, and chromatin conformation. X-chromosome inactivation (XCI) silences transcription from one X chromosome in female mammals, on which most genes are inactive, and some genes escape from XCI. In TS, almost all differentially expressed escape genes are down-regulated but most differentially expressed inactive genes are up-regulated. In KS, differentially expressed escape genes are up-regulated while the majority of inactive genes appear unchanged. Interestingly, 94 differentially expressed genes (DEGs) overlapped between TS and female and KS and male comparisons; and these almost uniformly display expression changes into opposite directions. DEGs on the X chromosome and the autosomes are coexpressed in both syndromes, indicating that there are molecular ripple effects of the changes in X chromosome dosage. Six potential candidate genes (RPS4X,SEPT6,NKRF,CX0rf57,NAA10, andFLNA) for KS are identified on Xq, as well as candidate central genes on Xp for TS. Only promoters of inactive genes are differentially methylated in both syndromes while escape gene promoters remain unchanged. The intrachromosomal contact map of the X chromosome in TS exhibits the structure of an active X chromosome. The discovery of shared DEGs indicates the existence of common molecular mechanisms for gene regulation in TS and KS that transmit the gene dosage changes to the transcriptome.

What microRNAs could tell us about the human X chromosome

“…This mechanism could partially account for the Turner syndrome-associated gonadal dysgenesis. miR-320 is not an X-linked miRNA, but its expression is modulated by KDM5C , encoded by an XCI-escaping gene [ 18 ], which is also differentially expressed in Turner syndrome [ 14 ]. Furthermore, a number of circulating miRNAs were differentially detected in 45,X Turner syndrome females as compared with 46,XX normal women, whose role should be further clarified [ 19 ].…”

“…In both syndromes no obvious genotype–phenotype relationship has so far been established, and patients carrying the same karyotype may exhibit widely differing traits, suggesting a role of epigenetic mechanisms behind sex chromosome aneuploidy [ 14 , 15 ]. So far, some studies have been dedicated to this issue, essentially based on the analysis of epigenetic mechanisms, as DNA methylation and histone modifications [ 16 , 17 ], and recently a dose effect for the number of X chromosomes has been shown to affect the expression profile for a range of mRNAs in a comparison of 45,X, 46,XX, 46,XY and 47,XXY individuals [ 18 ], implying that a similar dose effect could be present for X-linked miRNAs. But hitherto, the contribution of miRNAs to the phenotype of these syndromes has very poorly investigated [ 19 – 21 ], even though the higher density of miRNAs mapped on the X chromosome and their recognized regulatory role in biological processes.…”

Increased occurrence of liver and gastrointestinal diseases and anaemia in women with Turner syndrome – a nationwide cohort study

“…Additionally, Turner syndrome individuals harbouring an isochromosome, are more prone to develop autoantibodies and autoimmune disease 38,39 . The specific genes involved in the predilection for autoimmune disease development in Turner syndrome have not been elucidated, although recent studies have identified genes that are differentially expressed and genetic pathways to be involved in immune processes 40 . Specifically, the gene CD40LG, which is down‐regulated in Turner syndrome, has been proposed to be linked with IBD and hepatitis 41,42 …”

Identification of common differentially expressed genes in Turner (45,X) and Klinefelter (47,XXY) syndromes using bioinformatics analysis

“…Although several studies have investigated the association between the karyotype and the severity of the clinical manifestations in TS (Al Alwan, Khadora, & Amir, 2014; Bispo et al, 2013) and a subset of phenotypic characteristics of TS and KS appear to display a linear dose‐dependent association with the number of sex chromosomes, including stature and performance in cognitive subdomains of language and visuospatial processing (Zhang et al, 2020); nevertheless, other phenotypic traits including the altered risk of several autoimmune disorders in both syndromes (Jørgensen et al, 2010; Scofield et al, 2008), cannot exclusively account for sex‐chromosome dosage compensation. In general, the mechanisms through which an extra or absent X chromosome determines the characteristics of KS and TS are poorly understood, and it has been hypothesized that the TS and KS phenotype may result from not only genomic imbalance owing to genes present on sex chromosomes, but also the additive effect on associated genes within a particular gene network with altered gene regulation due to epigenetic factors (Álvarez‐Nava & Lanes, 2018).…”