Abstract
SummaryX 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.
Highlights
In humans and other mammalian species, female cells have two copies of the X chromosome, whereas males have a single X chromosome and a much smaller Y chromosome that is not present in females
We explore the global consequences for human gene expression when X chromosome inactivation (XCI) is eroded by using a collection of induced pluripotent stem cells (iPSCs) derived from healthy female donors that were all reprogrammed from primary skin fibroblasts (Kilpinen et al, 2017)
IPSC lines derived from healthy female donors and 46 lines derived from healthy male donors
Summary
In humans and other mammalian species, female cells have two copies of the X chromosome, whereas males have a single X chromosome and a much smaller Y chromosome that is not present in females. One of the two X chromosomes undergoes silencing, causing repression of transcription and thereby inactivating expression of alleles located on this second copy of the X. This process is termed X chromosome inactivation (XCI). XCI is vital for embryonic development, and failure to induce XCI has been shown to cause embryonic lethality (Borensztein et al, 2017; Takagi and Abe, 1990). Skewed XCI has been shown to have major clinical consequences, with the emergence of numerous sex-specific genetic disorders, such as Rett’s syndrome (Lyst and Bird, 2015)
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