Coordinated Histone Methylation Loss and MYC Activation Promote Translational Capacity Under Amino Acid Restriction

Epigenetic mechanisms underlying cellular adaptation to and recovery from nutrient deficiency are incompletely understood. Here, we report an adaptive epigenetic response to amino acid (AA) restriction that primes cells for rapid recovery. Depriving human cells of AAs led to selective loss of histone H4 lysine 20 monomethylation (H4K20me1) from gene bodies and increased MYC binding at promoters genome-wide, with strongest effects at ribosomal protein and translation initiation genes. Although AA restriction reduced overall protein synthesis, it was accompanied by increased translational capacity through upregulation of protein synthesis genes and accumulation of monomeric ribosomes. Combined SETD8, the H4K20 methyltransferase, depletion and MYC over-expression in nutrient-rich media was necessary and sufficient to recapitulate the transcriptional and functional effects of AA restriction. These findings suggest that cells respond to AA deprivation through coordinated chromatin and transcriptional changes that anticipate nutrient restoration and promote rapid recovery of protein synthesis when AAs are replenished.