Global analysis of functional relationships between histone point mutations and the effects of histone deacetylase inhibitors

Comprehensive analyses of the histone-GLibrary in previous studies showed that most mutants of modification sites in the histone core regions show phenotypes, whereas those with modifications in the histone N-terminal unstructured tail regions (N-tails) do not. One possible reason is that modifications in N-tails are linked to each other to form a scale-free network termed histone 'modification web'. In the network, the compensatory pathways are created to acquire the robustness against the any defects. Because of this robustness, it is difficult to determine the significance of the individual histone modifications in N-tails in vivo. To overcome this problem, we used a strategy using drugs coordinately to inhibit modification enzymes and observed the mutant phenotypes when the compensatory pathways are largely interrupted. We analyzed histone-GLibrary using inhibitors of histone deacetylases (HDACs) and identified novel phenotypic mutants. We also examined the phenotypic changes through the combined use of an HDAC inhibitor and an inhibitor of DNA-mediated reactions. Mutation of modifiable sites H3-K4 and H4-K16 in histone N-tails, which are presumed to be the 'hubs' of the network, resulted in identifiable phenotypes. The data obtained provide valuable information for speculation on novel relationships between histone modification in N-tails and biological function and for predicting unknown modification sites in core histones.