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

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

doi:10.1073/pnas.1910003117

New Research In

Contributed by Wing Hung Wong, January 16, 2020 (sent for review June 20, 2019; reviewed by Carolyn J. Brown and Joseph F. Cubells)

Significance

Turner syndrome (TS) is caused by having only one X chromosome (X0), and Klinefelter syndrome (KS) by having two X chromosomes and one Y chromosome (XXY). In this study we carried out a direct comparison analysis of the effect these chromosome copy number aberrations have on gene expression networks, analyzing genes located on the X chromosome or anywhere else in the genome, in primary samples from KS and TS patients. In both KS and TS, we found gene expression level changes not only in genes on the X chromosome, but also in many genes on all the other chromosomes, revealing a genomewide ripple effect of the chromosome X copy number aberrations.

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, 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.

Footnotes

↵¹X.Z., D.H., and S.M. contributed equally to this work.
↵²To whom correspondence may be addressed. Email: dshong{at}stanford.edu, whwong{at}stanford.edu, areiss1{at}stanford.edu, or aeurban{at}stanford.edu.

Author contributions: D.H., A.L.R., and A.E.U. designed research; X.Z., J.H., and A.E.U. performed research; T.W., M.H., R.P., Z.D., A.S., and S.B.S. contributed new reagents/analytic tools; X.Z., D.H., and S.M. analyzed data; X.Z., D.H., S.M., W.H.W., and A.E.U. wrote the paper; and W.H.W. supervised analysis/interpretation.
Reviewers: C.J.B., University of British Columbia; and J.F.C., Emory University School of Medicine.
The authors declare no competing interest.
Data deposition: RNA-Seq, DNA methylation, and in situ Hi-C data from this study have been deposited to GEO under accession no. GSE126712.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1910003117/-/DCSupplemental.

This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

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