The structural basis of histone modifying enzyme specificity and promiscuity: Implications for metabolic regulation...

Histone modifying enzymes regulate chromatin architecture through covalent modifications and ultimately control multiple aspects of cellular function. Disruption of histone modification leads to changes in gene expression profiles and may lead to disease. Both small molecule inhibitors and intermediary metabolites have been shown to modulate histone modifying enzyme activity although our ability to identify successful drug candidates or novel metabolic regulators of these enzymes has been limited. Using a combination of large scale in silico screens and in vivo phenotypic analysis, we identified several small molecules and intermediary metabolites with distinctive HME activity. Our approach using unsupervised learning identifies the chemical fingerprints of both small molecules and metabolites that facilitate recognition by the enzymes active sites which can be used as a blueprint to design novel inhibitors. Furthermore, this work supports the idea that histone modifying enzymes sense intermediary metabolites integrating genes, environment and cellular physiology.