Histone H3 lysine 4 trimethylation regulates cotranscriptional H2A variant exchange by Tip60 complexes to maximize gene expression

Thomas Kusch, Amanda Mei, Camtu Nguyen
Proceedings of the National Academy of Sciences of the United States of America 2014 April 1, 111 (13): 4850-5
Histone H3 lysine 4 trimethylation (H3K4me3) and the acetylated H2A variant, H2A.Z/v (H2Avac), are enriched at promoters of highly transcribed loci including the stress response genes. Using the inducible Drosophila hsp70 loci as a model, we study here the roles of the dSet1 and dTip60 complexes in the generation of these two chromatin modifications. We find that Heat Shock Factor recruits the dTip60 complex to the hsp70 loci in cells treated with salicylate, which triggers chromatin remodeling at these loci without transcription activation. Under these conditions, H2Avac or H3K4me3 are not enriched at the hsp70 promoter. By contrast, heat shock-induced hsp70 transcription induces dSet1-dependent H3K4me3 and H2Avac deposition by the dTip60 complex. The loss of dSet1 or dTip60 abolishes H2Avac incorporation, impairs Pol II release from the hsp70 promoter, and causes a stalling of mRNA production during phases of transcription maximization. Biochemical assays confirm that nucleosomal H3K4me3 stimulates the histone acetyltransferase and H2Av exchange activities of dTip60 complexes. H2Avac contributes to nucleosome destabilization at promoters, and H3K4me3 restricts its incorporation to phases of acute transcription. The process uncouples cotranscriptional chromatin remodeling by dTip60 complexes from their role in the activation of PARP, which is responsible for the removal of transcription-incompatible or damaged chromatin during the initial stress response. The control of the multifunctional dTip60 complex by H3K4me3 ensures optimal stress response and cell survival by mediating the rapid maximization of hsp70 expression. Furthermore, this mechanism prevents the accumulation of epigenetic noise caused by random complex-nucleosome collisions.

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