title: Nucleocytosolic acetyl-coenzyme a synthetase is required for histone acetylation and global transcription.
abstract: Metabolic enzymes rarely regulate informational processes like gene expression. Yeast acetyl-CoA synthetases (Acs1p and 2p) are exceptional, as they are important not only for carbon metabolism but also are shown here to supply the acetyl-CoA for histone acetylation by histone acetyltransferases (HATs). acs2-Ts mutants exhibit global histone deacetylation, transcriptional defects, and synthetic growth defects with HAT mutants at high temperatures. In glycerol with ethanol, Acs1p is an alternate acetyl-CoA source for HATs. Rapid deacetylation after Acs2p inactivation suggests nuclear acetyl-CoA synthesis is rate limiting for histone acetylation. Different histone lysines exhibit distinct deacetylation rates, with N-terminal tail lysines deacetylated rapidly and H3 lysine 56 slowly. Yeast mitochondrial and nucleocytosolic acetyl-CoA pools are biochemically isolated. Thus, acetyl-CoA metabolism is directly linked to chromatin regulation and may affect diverse cellular processes in which acetylation and metabolism intersect, such as disease states and aging.
authors.affiliation: High Throughput Biology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Takahashi
authors.forename: J Michael
authors.initials: JM
authors.lastname: McCaffery
authors.forename: Rafael A
authors.initials: RA
authors.lastname: Irizarry
authors.forename: Jef D
authors.initials: JD
authors.lastname: Boeke
mesh_terms: D000106:Acetate-CoA Ligase / Q000235:genetics / Q000502:physiology*; D000107:Acetylation; D002467:Cell Nucleus / Q000737:chemistry / Q000201:enzymology*; D003066:Coenzyme A Ligases / Q000235:genetics / Q000502:physiology*; D003600:Cytosol / Q000737:chemistry / Q000201:enzymology*; D051548:Histone Acetyltransferases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: D006657:Histones; D029701:Saccharomyces cerevisiae Proteins; D051548:Histone Acetyltransferases; D003066:Coenzyme A Ligases; D000106:Acetate-CoA Ligase; C561832:Acsl1 protein, rat