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

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 o...

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Bibliographic Details
Published in:Cell reports (Cambridge) 2021-04, Vol.35 (4), p.109032, Article 109032
Main Authors: Brenes, Alejandro J., Yoshikawa, Harunori, Bensaddek, Dalila, Mirauta, Bogdan, Seaton, Daniel, Hukelmann, Jens L., Jiang, Hao, Stegle, Oliver, Lamond, Angus I.
Format: Article
Language:English
Subjects:
dosage compensation
erosion of X chromosome inactivation
Female
gene expression
Humans
Induced Pluripotent Stem Cells - metabolism
iPSC
mass spectrometry
proteome
Proteome - metabolism
proteomics
RNA-seq
transcriptome
X chromosome inactivation
X Chromosome Inactivation - genetics
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Summary: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. [Display omitted] •iPSCs with eroded XCI show defective dosage compensation at the protein level•iPSCs with eroded XCI display elevated total protein content•iPSCs with eroded XCI show increased ribosome and polysome levels•Eroded XCI increases protein but not mRNA expression for 21% of autosomal genes X chromosome inactivation (XCI) is a dosage compensation mechanism in female mammals. Brenes et al. show how erosion of XCI affects mRNA and protein expression in humans and uncover a major impact on global protein translation when XCI is eroded, affecting protein expression from autosomal as well as X-linked genes.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2021.109032