Integrated Functional Genomic Analyses of Klinefelter and Turner Syndromes Reveal Global Network Effects of Altered X Chromosome Dosage

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2020 Feb 20

PMID 32071206

Citations 47

Authors

Xianglong Zhang

David Hong

Shining Ma

Thomas Ward

Marcus Ho

Reenal Pattni

Zhana Duren

Atanas Stankov

Sharon Bade Shrestha

Joachim Hallmayer

Wing Hung Wong

Allan L Reiss

Alexander E Urban

Affiliations

Soon will be listed here.

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 (, , , , , and ) 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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References

Tukiainen T, Villani A, Yen A, Rivas M, Marshall J, Satija R . Landscape of X chromosome inactivation across human tissues. Nature. 2017; 550(7675):244-248. PMC: 5685192. DOI: 10.1038/nature24265. View

Bakalov V, Cheng C, Zhou J, Bondy C . X-chromosome gene dosage and the risk of diabetes in Turner syndrome. J Clin Endocrinol Metab. 2009; 94(9):3289-96. PMC: 2741724. DOI: 10.1210/jc.2009-0384. View

Winge S, Dalgaard M, Jensen J, Graem N, Schierup M, Juul A . Transcriptome profiling of fetal Klinefelter testis tissue reveals a possible involvement of long non-coding RNAs in gonocyte maturation. Hum Mol Genet. 2017; 27(3):430-439. DOI: 10.1093/hmg/ddx411. View

Rao S, Huntley M, Durand N, Stamenova E, Bochkov I, Robinson J . A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell. 2014; 159(7):1665-80. PMC: 5635824. DOI: 10.1016/j.cell.2014.11.021. View

Rajpathak S, Deobagkar D . Evidence for epigenetic alterations in Turner syndrome opens up feasibility of new pharmaceutical interventions. Curr Pharm Des. 2013; 20(11):1778-85. DOI: 10.2174/13816128113199990518. View

Langfelder P, Horvath S . WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics. 2008; 9:559. PMC: 2631488. DOI: 10.1186/1471-2105-9-559. View

Nielsen J, Wohlert M . Chromosome abnormalities found among 34,910 newborn children: results from a 13-year incidence study in Arhus, Denmark. Hum Genet. 1991; 87(1):81-3. DOI: 10.1007/BF01213097. View

Viana J, Pidsley R, Troakes C, Spiers H, Wong C, Al-Sarraj S . Epigenomic and transcriptomic signatures of a Klinefelter syndrome (47,XXY) karyotype in the brain. Epigenetics. 2014; 9(4):587-99. PMC: 4121369. DOI: 10.4161/epi.27806. View

Lleo A, Moroni L, Caliari L, Invernizzi P . Autoimmunity and Turner's syndrome. Autoimmun Rev. 2011; 11(6-7):A538-43. DOI: 10.1016/j.autrev.2011.11.015. View

10.

Lachlan K, Youings S, Costa T, Jacobs P, Thomas N . A clinical and molecular study of 26 females with Xp deletions with special emphasis on inherited deletions. Hum Genet. 2005; 118(5):640-51. DOI: 10.1007/s00439-005-0081-1. View

11.

Cheng S, Rauen K, Pinkel D, Albertson D, Cotter P . Xq chromosome duplication in males: clinical, cytogenetic and array CGH characterization of a new case and review. Am J Med Genet A. 2005; 135(3):308-13. DOI: 10.1002/ajmg.a.30613. View

12.

Hong D, Reiss A . Cognitive and neurological aspects of sex chromosome aneuploidies. Lancet Neurol. 2014; 13(3):306-18. DOI: 10.1016/S1474-4422(13)70302-8. View

13.

Darrow E, Huntley M, Dudchenko O, Stamenova E, Durand N, Sun Z . Deletion of DXZ4 on the human inactive X chromosome alters higher-order genome architecture. Proc Natl Acad Sci U S A. 2016; 113(31):E4504-12. PMC: 4978254. DOI: 10.1073/pnas.1609643113. View

14.

Massingham L, Johnson K, Scholl T, Slonim D, Wick H, Bianchi D . Amniotic fluid RNA gene expression profiling provides insights into the phenotype of Turner syndrome. Hum Genet. 2014; 133(9):1075-82. PMC: 4384642. DOI: 10.1007/s00439-014-1448-y. View

15.

Wan E, Qiu W, Morrow J, Beaty T, Hetmanski J, Make B . Genome-wide site-specific differential methylation in the blood of individuals with Klinefelter syndrome. Mol Reprod Dev. 2015; 82(5):377-86. PMC: 4439255. DOI: 10.1002/mrd.22483. View

16.

Bojesen A, Gravholt C . Klinefelter syndrome in clinical practice. Nat Clin Pract Urol. 2007; 4(4):192-204. DOI: 10.1038/ncpuro0775. View

17.

Sharma A, Jamil M, Nuesgen N, Schreiner F, Priebe L, Hoffmann P . DNA methylation signature in peripheral blood reveals distinct characteristics of human X chromosome numerical aberrations. Clin Epigenetics. 2015; 7:76. PMC: 4517491. DOI: 10.1186/s13148-015-0112-2. View

18.

Geerkens C, Just W, Vogel W . Deletions of Xq and growth deficit: a review. Am J Med Genet. 1994; 50(2):105-13. DOI: 10.1002/ajmg.1320500202. View

19.

Ciccodicola A, DEsposito M, Esposito T, Gianfrancesco F, Migliaccio C, Miano M . Differentially regulated and evolved genes in the fully sequenced Xq/Yq pseudoautosomal region. Hum Mol Genet. 2000; 9(3):395-401. DOI: 10.1093/hmg/9.3.395. View

20.

Zitzmann M, Bongers R, Werler S, Bogdanova N, Wistuba J, Kliesch S . Gene expression patterns in relation to the clinical phenotype in Klinefelter syndrome. J Clin Endocrinol Metab. 2014; 100(3):E518-23. DOI: 10.1210/jc.2014-2780. View