April 2021

The lab has a new publication Erosion of human X chromosome inactivation causes major remodeling of the iPSC proteome in Cell Reports.

X chromosome inactivation (XCI) is a dosage compensation mechanism in females whereby transcription from one X-chromosome is repressed. Using human induced pluripotent stem cells (iPSCs), Brenes et al., identify how erosion of XCI affects mRNA and protein expression in humans and uncover a major impact on global protein translation when XCI is eroded.

They found that erosion of XCI disrupts dosage compensation at the protein level, as female iPSCs with an eroded X chromosome displayed significantly higher X-linked mRNA and protein content than male iPSCs. However, they also discovered that this effect was not limited to proteins encoded on the X chromosome. Thousands of autosome encoded proteins were also significantly increased in expression in eroded iPSCs compared to female iPSCs with robust XCI and also compared to male iPSCs. This novel autosomal effect was not visible within the RNA-seq.

In their manuscript they propose a mechanism whereby erosion of XCI inactivation increases the expression levels of X-linked proteins, mainly via a transcriptional mechanism, and this in turn modulates protein translation thereby increasing the expression of thousands of autosomal proteins. This work has important consequences for disease progression and sex specific response to therapy, as it shows that erosion of XCI affects the expression of a much wider range of proteins and disease-linked loci than was previously realised. It also highlights the importance of sex specific studies as there are still many uncharacterised differences between females and males that need to be better understood in order to advance precision medicine.

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