title: Metabolic Regulation of Histone Acetyltransferases by Endogenous Acyl-CoA Cofactors.
abstract: The finding that chromatin modifications are sensitive to changes in cellular cofactor levels potentially links altered tumor cell metabolism and gene expression. However, the specific enzymes and metabolites that connect these two processes remain obscure. Characterizing these metabolic-epigenetic axes is critical to understanding how metabolism supports signaling in cancer, and developing therapeutic strategies to disrupt this process. Here, we describe a chemical approach to define the metabolic regulation of lysine acetyltransferase (KAT) enzymes. Using a novel chemoproteomic probe, we identify a previously unreported interaction between palmitoyl coenzyme A (palmitoyl-CoA) and KAT enzymes. Further analysis reveals that palmitoyl-CoA is a potent inhibitor of KAT activity and that fatty acyl-CoA precursors reduce cellular histone acetylation levels. These studies implicate fatty acyl-CoAs as endogenous regulators of histone acetylation, and suggest novel strategies for the investigation and metabolic modulation of epigenetic signaling.
authors.affiliation: Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick MD, 21702, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Montgomery
authors.affiliation: Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick MD, 21702, USA.
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Sorum
authors.affiliation: Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick MD, 21702, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Guasch
authors.affiliation: Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick MD, 21702, USA.
authors.forename: Marc C
authors.initials: MC
authors.lastname: Nicklaus
authors.affiliation: Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick MD, 21702, USA.
authors.forename: Jordan L
authors.initials: JL
authors.lastname: Meier
mesh_terms: D000107:Acetylation; D000214:Acyl Coenzyme A / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D051046:Amino-Acid N-Acetyltransferase / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells; D051548:Histone Acetyltransferases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008239:Lysine / Q000737:chemistry / Q000378:metabolism*; D008956:Models, Chemical; D010171:Palmitoyl Coenzyme A / Q000737:chemistry / Q000378:metabolism; D040901:Proteomics
chemical_list: D000214:Acyl Coenzyme A; D010171:Palmitoyl Coenzyme A; D051046:Amino-Acid N-Acetyltransferase; D051548:Histone Acetyltransferases; D008239:Lysine