34 | 2025 GIGA Annual Report WEL Research Institute projects 2024 Alain Chariot Laboratory of Medical Chemistry Translational reprogramming helps cancer cells to support cell survival and proliferation. This process is regulated by tRNA modifications. Many diseases are characterized by a deregulated translational reprogramming. The tRNA-modifying enzyme is acting as an oncogenic protein in the intestine and in the mammary gland. We recently showed that Elp3 deficiency in hepatocytes leads to lethality post-birth due to lower glucose levels. We will explore how Elp3 promotes cell differentiation in the liver and we will define new Elp3 targets involved in gluconeogenesis. Elp3 deficiency in adipocytes potentiates the gain of weight in mice subjected to a high fat diet. We will identify new actors involved in adipocyte hypertrophy whose mRNA translation is regulated by Elp3. We will also explore whether and how the loss of Elp3 in adipocytes sensitizes mice to obesity-driven liver cancer. Finally, we will address the role of the prolylhydroxylase Lepre-1, a candidate whose expression is regulated by Elp3, in tumor initiation and progression up to metastasis in the intestine. Collectively, our project will shed new lights into mechanisms through which some tRNA modifications are involved in the biology of both hepatocytes and adipocytes with important consequences in hepatic metabolism, obesity and obesity-driven liver cancer. We will also establish the landscape of proline hydroxylation during tumor development in the intestine. ALAIN CHARIOT TRANSLATIONAL REPROGRAMMING THROUGH tRNA MODIFICATIONS IN HEALTH AND DISEASES
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