Illuminating the dark proteome: Insights from RNA translation in health and disease

RNA translation is a fundamental process in gene expression, yet its extent, role and regulation in human diseases remain unclear. In my talk, I will describe how our data-driven approaches to study RNA translation have revealed a substantial portion of gene expression activity that has been overlooked when studying diseases. This has led to 1) a paradigm shift in that human transcripts often translate multiple distinct open reading frames (ORFs), 2) a 40% increase in translated ORFs encoded in the human genome including within lncRNAs and 3) detection of widespread gene expression changes that were previously missed in traditional RNA-based target discovery screens. These findings highlight a largely untapped search-space for new biomarkers, therapeutic targets and antigens for targeted therapy. Additionally, the algorithms developed provide a powerful platform to gain insights on the translatome in any given system, as demonstrated by our work in fibrosis, inflammation, and cancer, paving the way for future breakthroughs in RNA biology.