Erosion of human X chromosome inactivation causes major remodeling of the iPSC proteome.

Alejandro J Brenes, Harunori Yoshikawa, Dalila Bensaddek, Bogdan Mirauta, Daniel Seaton, Jens L Hukelmann, Hao Jiang, Oliver Stegle, Angus I Lamond

    Research output: Contribution to journalArticlepeer-review

    18 Scopus citations

    Abstract

    X 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.
    Original languageEnglish (US)
    Pages (from-to)109032
    JournalCell reports
    Volume35
    Issue number4
    DOIs
    StatePublished - Apr 28 2021

    Bibliographical note

    KAUST Repository Item: Exported on 2021-05-03
    Acknowledgements: We 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.

    ASJC Scopus subject areas

    • General Biochemistry, Genetics and Molecular Biology

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