Erosion of human X chromosome inactivation causes major remodeling of the iPSC proteome.
AuthorsBrenes, Alejandro J
Hukelmann, Jens L
Lamond, Angus I
KAUST DepartmentProteomics, protein expression & cytomet
Permanent link to this recordhttp://hdl.handle.net/10754/669034
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AbstractX chromosome inactivation (XCI) is a dosage compensation mechanism in female mammals whereby transcription from one X chromosome is repressed. Analysis of human induced pluripotent stem cells (iPSCs) derived from female donors identified that low levels of XIST RNA correlated strongly with erosion of XCI. Proteomic analysis, RNA sequencing (RNA-seq), and polysome profiling showed that XCI erosion resulted in amplified RNA and protein expression from X-linked genes, providing a proteomic characterization of skewed dosage compensation. Increased protein expression was also detected from autosomal genes without an mRNA increase, thus altering the protein-RNA correlation between the X chromosome and autosomes. XCI-eroded lines display an ∼13% increase in total cell protein content, with increased ribosomal proteins, ribosome biogenesis and translation factors, and polysome levels. We conclude that XCI erosion in iPSCs causes a remodeling of the proteome, affecting the expression of a much wider range of proteins and disease-linked loci than previously realized.
CitationBrenes, A. J., Yoshikawa, H., Bensaddek, D., Mirauta, B., Seaton, D., Hukelmann, J. L., … Lamond, A. I. (2021). Erosion of human X chromosome inactivation causes major remodeling of the iPSC proteome. Cell Reports, 35(4), 109032. doi:10.1016/j.celrep.2021.109032
SponsorsWe thank all of our collaborators who worked on the HipSci project as well as D. Cantrell, M. Stavridis, G. Findlay, J. Marchingo, and F. Dossin for all the insightful discussions. We would also like to thank L. Davidson within the University of Dundee Stem Cell Facility and all members of the Lamond Laboratory. This work was funded by the Wellcome Trust/MRC (098503/E/12/Z) and Wellcome Trust grants (073980/Z/03/Z and 105024/Z/14/Z) and supported by a UK Research Partnership Infrastructure Fund award to the Centre for Translational and Interdisciplinary Research.
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