Erosion of human X chromosome inactivation alters proteome expression from genes across the X chromosome and all autosomes

Integrated analysis using proteomics, RNAseq and polysome profiles revealed a major impact on the proteome caused by erosion of X chromosome inactivation (XCI) in human iPSCs. Low XIST RNA levels were detected in ~40% of iPSC lines from healthy female donors and strongly correlated with erosion of XCI, as evaluated by biallelic expression. Low XIST levels correlated with increased RNA and protein expression from X-linked genes, a ~13% increase in total cell protein content, and significantly increased levels of polysomes, ribosomes and translation factors. Low XIST lines also showed increased protein expression for many autosomal genes, but without a corresponding mRNA increase, producing a major difference in the protein-RNA correlation between genes on either the X chromosome, or autosomes. We conclude that erosion of XCI causes a major remodelling of the proteome, with posttranscriptional mechanisms affecting the expression of a much wider range of proteins and disease-linked gene loci than previously realised.