Translation maps the transcriptome onto the proteome. It is regulated at the initiation levels and also by mRNA secondary structure, and – our current focus – by the interplay between the mRNA and tRNA pools. Although a lot is known about the mechanics of translation, its effects on physiology, particularly on proliferation and differentiation in mammals presents major open questions.tRNAProlif offers an approach that consists of genome-wide measurements and analyses of the tRNA and mRNAs pools, and the interplay between them, in proliferative and differentiated cells. The project will explain how changes in translation affect, and are affected by, these two states.We rely on our preliminary results that show a striking dichotomy in codon usage: genes involved in cellular proliferation have distinct codon usage compared to genes involved in differentiation and other multi-cellular process. Further, the tRNA pool consists of two distinct sub-populations: tRNAs whose codons are enriched among the proliferation genes are induced in proliferation and cancer, and tRNAs whose codons are enriched in differentiation genes are repressed in proliferation and are induced in differentiation. Towards understanding this “tRNA Switch” we aim at:Causality: We will determine whether the tRNA pool affects the proliferation/differentiation status of cell. Conversely, we will determine the effects of the proliferation/differentiation status on the tRNA pool.Regulation: We will establish the regulatory scheme that governs the “tRNA Switch”: we will determine the effects of transcriptional and post-transcriptional regulation on the tRNAs, depending on cell state. We will determine how the balance between the two tRNA sub-populations affects the proteome.Evolution: We will conduct comparative genomics of regulation of tRNA availability and codon usage and its effect on physiology in multiple species.