2. Academic Validation
  3. HAT1 Coordinates Histone Production and Acetylation via H4 Promoter Binding

HAT1 Coordinates Histone Production and Acetylation via H4 Promoter Binding

  • Mol Cell. 2019 Aug 22;75(4):711-724.e5. doi: 10.1016/j.molcel.2019.05.034.
Joshua J Gruber 1,  Benjamin Geller 2,  Andrew M Lipchik 2,  Justin Chen 2,  Ameen A Salahudeen 3,  Ashwin N Ram 2,  James M Ford 1,  Calvin J Kuo 3,  Michael P Snyder 4
Affiliations

Affiliations

  • 1 Department of Medicine, Oncology Division, Stanford School of Medicine, Stanford University, Palo Alto, CA 94304, USA; Department of Genetics, Stanford School of Medicine, Stanford University, Palo Alto, CA 94304, USA.
  • 2 Department of Genetics, Stanford School of Medicine, Stanford University, Palo Alto, CA 94304, USA.
  • 3 Department of Medicine, Hematology Division, Stanford School of Medicine, Stanford University, Palo Alto, CA 94304, USA.
  • 4 Department of Genetics, Stanford School of Medicine, Stanford University, Palo Alto, CA 94304, USA. Electronic address: [email protected].
PMID: 31278053 DOI: 10.1016/j.molcel.2019.05.034
Abstract

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.

Keywords

H3K9Ac; H4K12Ac; H4K5Ac; HAT1; acetate; acetyl-Co-A; cancer metabolism; chromatin replication; histone H4; nutrient sensing.

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