Histone Demethylation and MYC Activation Enhance Translational Capacity in Response to Amino Acid Restriction
Nutrient limitation may elicit adaptive epigenetic changes but the nature and mechanisms of the cellular response to specific nutrient deficiencies are incompletely understood. We report that depriving human cells of amino acids (AAs) induces specific loss of histone H4 lysine 20 monomethylation (H4K20me1) from gene bodies and elevated binding of MYC at promoters genome-wide. These effects are most pronounced at ribosomal protein and translation initiation genes, which are transcriptionally upregulated, leading to enhanced protein synthetic capacity. Combination of SETD8, the H4K20 methyltransferase, depletion and MYC over-expression in rich media is required and sufficient to recapitulate the effects of AA restriction transcriptionally and functionally. Our data reveal an unexpected and epigenetically implemented increase in translational capacity when AAs are limiting. This adaptive response likely safeguards the proteome by making effective use of limited resources, and prepares the cell for swift initiation of protein synthesis when AAs are replenished.