Integrated functional genomic analyses of Klinefelter and Turner syndromes reveal global network effects of altered X chromosome dosage
Open accessAbstract
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 , and FLNA ) 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.
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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 [105]
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Clinical practice guidelines for the care of girls and women with Turner syndrome.
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- Authors
- Zhang, X., Hong, D., Ma, S., Ward, T., Ho, M., Pattni, R., Duren, Z., Stankov, A., Bade Shrestha, S., Hallmayer, J., Wong, W. H., Reiss, A. L., & Urban, A. E.
- Affiliations
- Stanford Medicine (US)
- Stanford University (US)
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305;
- Corresponding author
- Hong, David
- Wong, Wing Hung
- Reiss, Allan L.
- Urban, Alexander E.
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2020-02-18
- Volume
- 117
- Issue
- 9
- Pages
- 4864-4873
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC7060706
- OpenAlex
- W3007250801
- Cited by
- 101
- References
- 55
- Citations by year
- 2026: 8 · 2025: 16 · 2024: 13 · 2023: 27 · 2022: 15 · 2021: 16 · 2020: 6
- FWCI
- 9.51
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Human Genome Research Institute (HG007735)
- 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 › Sexual Differentiation and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- Klinefelter syndrome, Turner syndrome, X chromosome dosage, X chromosome inactivation, copy number alterations, gene expression, DNA methylation, chromatin conformation, co-expression network, candidate genes, RPS4X, SEPT6, NAA10, filamin A
- MeSH terms
- Animals, Chromatin, Female, Gene Expression Regulation, Humans, Klinefelter Syndrome, Male, Mammals, Repressor Proteins, Turner Syndrome, X Chromosome, Protein Serine-Threonine Kinases, Gene Dosage, DNA Methylation, Genomics, Chromosomes, Human, X, Receptor, PAR-2, X Chromosome Inactivation, Septins, Transcriptome, Karyotype, N-Terminal Acetyltransferase A, N-Terminal Acetyltransferase E, Filamins
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