HAT1 Coordinates Histone Production and Acetylation via H4 Promoter Binding

The energetic costs of duplicating chromatin are large and therefore likely depend on nutrient sensing checkpoints and metabolic inputs. By studying chromatin modifiers regulated by epithelial growth factor, we identified histone acetyltransferase 1 (HAT1) as an induced gene that enhances proliferation through coordinating histone production, acetylation, and glucose metabolism. In addition to its canonical role as a cytoplasmic histone H4 acetyltransferase, we isolated a HAT1-containing complex bound specifically at promoters of H4 genes. HAT1-dependent transcription of H4 genes required an acetate-sensitive promoter element. HAT1 expression was critical for S-phase progression and maintenance of H3 lysine 9 acetylation at proliferation-associated genes, including histone genes. Therefore, these data describe a feedforward circuit whereby HAT1 captures acetyl groups on nascent histones and drives H4 production by chromatin binding to support chromatin replication and acetylation. These findings have important implications for human disease, since high HAT1 levels associate with poor outcomes across multiple cancer types. [Display omitted] •HAT1 is an EGF-stimulated acetyltransferase required for EGF-dependent growth•HAT1 holoenzyme specifically binds to histone H4 promoters•Histone H4 promoters contain an acetate-sensitive genomic element•HAT1 expression is associated with poor cancer outcomes in humans and mice Nascent histone H4 is acetylated by cytoplasmic histone acetyltransferase 1 (HAT1) and then de-acetylated after chromatin insertion, releasing free acetate. Gruber et al. discover that HAT1 also binds an acetate-sensitive promoter element in histone H4 genes. Therefore, histone production and acetylation are linked by HAT1 to drive cell division via acetyl-Co-A regeneration.