Abstract 113: Defining the metabolic regulation of epigenetics using chemical proteomics

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 restore balance in metabolically-perturbed cancers. Towards this goal, here we report a strategy to directly define the metabolic regulation of epigenetic signaling using chemical proteomics. Our initial efforts have focused on understanding the metabolic regulation of lysine acetyltransferases (KATs), a major class of chromatin modifiers responsible for protein acetylation. We demonstrate that chemoproteomic probes can report on the interaction of acyl-CoA metabolites with KAT active sites, and when combined with affinity purification and LC-MS/MS analysis, highlight an expanded landscape of acetyltransferases present in the human genome. Next-generation chemoproteomic methods highlight the interactions of metabolic acyl-CoAs with megadalton lysine acetyltransferase protein complexes, which have implications for the regulation of KAT activity by cellular acyl-CoA pools. By defining the molecular links connecting metabolism and gene expression,these approaches will illuminate our understanding of cancer biology and inspire new therapeutic strategies to combat cancer. Citation Format: Jordan L. Meier, David C. Montgomery, Alexander W. Sorum, Rhushikesh A. Kulkarni. Defining the metabolic regulation of epigenetics using chemical proteomics. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 113. doi:10.1158/1538-7445.AM2015-113