Cross Talk between Histone Modifications in Response to Hdac Inhibitors: Mll4 Links Histone H3 Acetylation and Histone H3k4 Methylation

Histones are subject to a wide variety of posttranslational modifications, which play a central role in gene activation and silencing. We have used histone modification-specific antibodies to demonstrate that two histone modifications involved in gene activation – histone H3 acetylation, and H3 lysine 4 methylation – are functionally linked. This interaction, in which the extent of histone H3 acetylation determines both the abundance and the ‘degree’ of H3K4 methylation plays a major role in the epigenetic response to histone deacetylase inhibitors. A combination of in vivo knockdown experiments, and in vitro methyl-transferase assays show that the abundance of H3K4 methylation is regulated by the activities of two opposing enzyme activities; the methyl-transferase MLL4, which is stimulated by acetylated substrates, and a novel and as yet unidentified H3K4me3 demethylase.