In this project, we will examine transcriptome complexity and RNA pool plasticity in mammalian systems with a special focus on RNA binding protein (RBP)-mediated post-transcriptional regulation in development and disease. We will focus on the identification of physiologically and pathologically relevant transcripts and RBPs. Candidates will be selected according to their degree of conservation across mammalian species and their expression profiles in development and liver disease, such as non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC). Through a multi-omics integrative approach, we will infer RBP-RNA networks and perform a comparative analysis across developmental and disease conditions. In addition, we will turn to specific non-coding RNA (ncRNA) species (e.g., tRNAs and lncRNAs) and investigate their interplay with RBPs and contribution to disease. Lastly, the impact of cellular heterogeneity in the tissue will be accounted for by incorporating single cell information into the analyses. We expect that the study of RNA pools and RBPs in control and disease conditions will yield critical insight into RBP-mediated post-transcriptional regulation in mammals and, in light of emerging RNA therapeutics, it may provide new prognostic and druggable targets to be used in the clinic to fight disease.