Erosion of human X chromosome inactivation alters proteome expression from genes across the X chromosome and all autosomes
Hukelmann, Jens L.
Lamond, Angus I.
KAUST DepartmentProteomics and Protein Expression
Permanent link to this recordhttp://hdl.handle.net/10754/662318
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AbstractSummary:Integrated analysis using proteomics, RNAseq and polysome profiles revealed a major impact on the proteome caused by erosion of X chromosome inactivation (XCI) in human iPSCs. Low XIST RNA levels were detected in ∼40% of iPSC lines from healthy female donors and strongly correlated with erosion of XCI, as evaluated by biallelic expression. Low XIST levels correlated with increased RNA and protein expression from X-linked genes, a ∼13% increase in total cell protein content, and significantly increased levels of polysomes, ribosomes and translation factors. Low XIST lines also showed increased protein expression for many autosomal genes, but without a corresponding mRNA increase, producing a major difference in the protein-RNA correlation between genes on either the X chromosome, or autosomes. We conclude that erosion of XCI causes a major remodelling of the proteome, with posttranscriptional mechanisms affecting the expression of a much wider range of proteins and disease-linked gene loci than previously realised.
CitationBrenes, A. J., Yoshikawa, H., Bensaddek, D., Mirauta, B., Seaton, D., Hukelmann, J. L., … Lamond, A. I. (2020). Erosion of human X chromosome inactivation alters proteome expression from genes across the X chromosome and all autosomes. doi:10.1101/2020.03.18.997049
SponsorsWe thank all of our collaborators who worked on the HipSci project. We would also like to thank D. Cantrell, M. Stavridis, G. Findlay, J. Marchingo and F. Dossin for all the insightful discussions as well as L. Davidson within the University of Dundee Stem Cell Facility. We would also like to thank members in the Lamond Laboratory for insightful discussions. Funding: This work was funded by the Wellcome Trust /MRC [098503/E/12/Z] and Wellcome Trust grants [073980/Z/03/Z, 105024/Z/14/Z]. Competing interests: Authors declare no competing interests. Data and materials availability: All of the mass-spectrometry raw files and the MaxQuant outputs have been uploaded to PRIDE and are publicly available under accession PXD10557. The RNAseq data has been uploaded to the ENA project are publicly available under accession PRJEB7388.
PublisherCold Spring Harbor Laboratory