Methylation-directed Acetylation of Histone H3 Regulates Developmental Sensitivity to Histone Deacetylase Inhibition

Abstract

BackgroundTreatment of cells with hydroxamate-based lysine deacetylase inhibitors (KDACis) such as Trichostatin A (TSA) can induce biological effects such as differentiation or apoptosis of cancer cells, and a number of related compounds have been approved for clinical use. TSA treatment induces rapid initial acetylation of histone 3 (H3) proteins which are already modified by tri-methylation on lysine 4 (H3K4me3) while acetylation of bulk histones, lacking this mark, is delayed. Sgf29, a subunit of the SAGA acetyltransferase complex, interacts with H3K4me3 via a tandem tudor domain (TTD) and has been proposed to target the acetyltransferase activity to H3K4me3. However the importance of acetylation of this pool of H3 in the biological consequences of KDACi treatment is not known. ResultsWe investigated the role of H3K4me3-directed acetylation in the mechanism of action of TSA on inhibiting development of the eukaryotic social amoeba Dictyostelium discoideum. Loss of H3K4me3 in strains with mutations in the gene encoding Set1 or the histone proteins confers resistance to TSA-induced inhibition of development and delays accumulation of histone acetylation on H3K9 and K14. A candidate orthologue of Sgf29 in Dictyostelium has been identified which specifically recognizes the H3K4me3 modification via its tandem Tudor domain (TTD). Disruption of the gene encoding Sgf29 delayed accumulation of H3K9Ac, abolished targeted H3K4me3-directed H3Ac and led to developmental resistance to TSA, which is dependent on a functional TTD. TSA resistance also results from overexpression of Sgf29. ConclusionPreferential acetylation of H3K4me3 histones, regulated by Sgf29 via its TTD, is important in developmental sensitivity to TSA. Levels of H3K4me3 or Sgf29 will provide useful biomarkers for sensitivity to this class of chemotherapeutic drug.