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

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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

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