"The human iPS Cell Proteome in Health & Disease"
Prof. Angus Lamond (Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee)
Deep mining of proteomes, using mass spectrometry (MS) based technology, can provide invaluable insights, at a systems level, into both physiological responses in healthy cells and mechanisms causing disease phenotypes. A further challenge concerns how to analyse and integrate these proteomic data with other parallel ‘omics’, cell phenotypic and clinical data and how to manage the large resulting volumes of complex information. I will describe our progress in using quantitative proteomics for the large-scale analysis of many human induced pluripotent stem cell lines (iPSCs). This includes analysis of iPSC lines derived from both healthy donors and patient cohorts with specific inherited disorders. We have thereby generated a deep proteome of human iPS cells and characterised the major determinants affecting both proteome and transcriptome variation across multiple human iPSC lines from healthy donors. This identified key regulatory mechanisms affecting differential protein and mRNA abundance. The data reveal >700 human iPSC protein quantitative trait loci (pQTLs), for which we mapped trans regulatory effects and demonstrated an increased enrichment in diseaselinked GWAS variants, compared with RNA-based eQTLs. Analysis of iPSC lines derived from healthy female donors showed that >40% expressed low levels of Xist RNA and had escaped from the normal inactivation of one of the two X chromosomes. We have characterised the impact of escape from X chromosome inactivation on the proteomes of female iPSC lines. This shows a general increase in total levels of polysomes and protein expression, which includes upregulation of the expression of multiple genes on somatic chromosomes via post-transcriptional mechanisms.