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

Alejandro J. Brenes (Lead / Corresponding author), Harunori Yoshikawa, Dalila Bensaddek, Bogdan Mirauta, Daniel D. Seaton, Jens Hukelmann, Hao Jiang, Oliver Stegle, Angus Lamond

    Research output: Contribution to journalArticlepeer-review

    22 Citations (Scopus)
    102 Downloads (Pure)

    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
    Article number109032
    Number of pages20
    JournalCell Reports
    Volume35
    Issue number4
    DOIs
    Publication statusPublished - 27 Apr 2021

    Keywords

    • RNA-seq
    • X chromosome inactivation
    • dosage compensation
    • erosion of X chromosome inactivation
    • gene expression
    • iPSC
    • mass spectrometry
    • proteome
    • proteomics
    • transcriptome

    ASJC Scopus subject areas

    • General Biochemistry,Genetics and Molecular Biology

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