Abstract 16602: Connecting Histone-Modifying Enzymes and Metabolism Through Chemical Probes and Network Pharmacology
Chromatin regulation plays a central role in the complex network of factors that control DNA based functions including accessibility for DNA repair, replication and transcription. Reversible covalent modifications by histone modifying enzymes (HMEs) provide an adaptable and dynamic platform for precise control of chromatin structure, gene expression and cell fates and have been shown to regulate disease progression. Although our understanding of chromatin regulation has dramatically improved, many of the epigenetic mechanisms cells use to adapt and integrate signals and environmental cues remain unknown. Here, we integrate the use and design of chemical probes to connect metabolism with plasticity and cardiovascular disease while identifying novel probes and metabolites capable of temporal modulation of HMEs.
We first used computational methods to identify candidate metabolic and small molecule regulators of > 75 HMEs. High throughput virtual docking studies predicted many high affinity HME-small molecule interactions. Bipartite networks were then constructed connecting chemical probes with HMEs. Unsupervised machine learning method were used to topologically cluster small molecule and metabolite libraries incorporating more than 150 unique chemical descriptors with a final quantization and topographic error of 7.44 and 0.08. We then empirically validated a subset of predicted interactions using biochemical assays and zebrafish phenotype clustering with an odds ratio for enrichment of 10. Novel metabolite regulation was identified by chemical similarity to small molecule-HME interactions and shown to influence cardiovascular phenotypes in zebrafish highlighting their potential role in development and disease.
This work provides a systematic approach to the exploration of metabolic control of epigenetic states and also enables the identification of new chemical probes of histone modifying enzyme activity. Furthermore, our data also implicates metabolic regulation in cardiovascular disease and development providing new evidence on the relationship between the levels of cellular metabolites and the cardiovascular epigenome.
- © 2013 by American Heart Association, Inc.