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 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 similar to 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.

Automated summary

X chromosome inactivation (XCI) leads to a remodeling of the proteome in human induced pluripotent stem cells (iPSCs), with increased RNA and protein expression from X-linked genes. XCI erosion affects both X-linked and autosomal genes' protein expression, ultimately impacting a wider range of proteins and disease-linked loci.