MAPPING THE TRANSLATIONAL LANDSCAPE IN HUMAN CARDIAC FIBROSIS AND BEYOND

Abstract

Genome-wide transcriptional changes have been widely studied, but due to challenges in data availability and computational methods, the impact of translational regulation in human diseases remains unclear. To address this, we developed an accurate computational approach, deltaTE, to quantify translational regulation, using transcription (RNA-seq) and translation (Ribo-seq) measurements. This approach outperformed published methods in three independent benchmarking analyses. We then applied deltaTE to assess translational regulation in human cardiac fibrosis, a key pathology underlying most cardiac diseases. Ribo-seq on fibroblast activation uncovered one-third of gene-expression changes in fibrosis as translationally regulated. Integration of CLIP-seq (Cross-linking immunoprecipitation) allowed an unprecedented view of RNA-binding proteins (RBPs) as key regulators of translation. Furthermore, Ribo-seq of 30 cardiomyopathy patient hearts revealed active RBP driven regulation and in-vitro silencing of two RBP network hubs, Pumilio-2 and Quaking, inhibited fibroblast activation. Taken together, our findings highlight widespread translational regulation in fibrosis with RBPs as emerging targets in cardiac diseases.