Abstract 3096: Mapping lysine acetyltransferase-metabolite interactions in complex proteomes: a window into the metabolic regulation of epigenetic signaling

Abstract

Abstract Substantial evidence indicates that chromatin modifiers are sensitive to changes in the cellular concentration of metabolites and cofactors. These findings potentially connect metabolism and gene expression, and have major implications for the regulation of cell signaling in cancer. However, missing from many of these studies has been the direct identification of the specific chromatin modifiers that sense change in metabolic state. Their identification is critical to our basic understanding of how metabolism regulates epigenetically-driven phenotypes, and may inform novel strategies to combat pathologies characterized by aberrant metabolism, including cancer. Towards this goal, here we report a chemical proteomic strategy to globally map chromatin modifier-metabolite interactions in complex proteomes. Our initial efforts have focused on lysine acetyltransferases (KATs), a central class of chromatin modifiers responsible for histone acetylation. First, we validate an optimized chemical proteomic method and demonstrate its ability to globally profile members of the KAT enzyme superfamily at endogenous expression levels. Then we apply this approach to rapidly profile KAT-ligand interactions, and identify novel candidate metabolic regulators of protein acetylation, including acyl-CoAs cofactors and metabolites, as well as new metabolically-sensitive KAT enzymes. By defining the molecular interactions linking metabolism and gene expression, these studies have the potential to illuminate our understanding of biology and inspire new therapeutic strategies targeting acetylation in disease. Citation Format: Jordan L. Meier. Mapping lysine acetyltransferase-metabolite interactions in complex proteomes: a window into the metabolic regulation of epigenetic signaling. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3096.