Abstract
Hydroxamate-based lysine deacetylase inhibitors (KDACis) are approved for clinical use against certain cancers. However, intrinsic and acquired resistance presents a major problem. Treatment of cells with hydroxamates such as trichostatin A (TSA) leads to rapid preferential acetylation of histone H3 already trimethylated on lysine 4 (H3K4me3), although the importance of this H3K4me3-directed acetylation in the biological consequences of KDACi treatment is not known. We address this utilizing Dictyostelium discoideum strains lacking H3K4me3 due to disruption of the gene encoding the Set1 methyltransferase or mutations in endogenous H3 genes. Loss of H3K4me3 confers resistance to TSA-induced developmental inhibition and delays accumulation of H3K9Ac and H3K14Ac. H3K4me3-directed H3Ac is mediated by Sgf29, a subunit of the SAGA acetyltransferase complex that interacts with H3K4me3 via a tandem tudor domain (TTD). We identify an Sgf29 orthologue in Dictyostelium with a TTD that specifically recognizes the H3K4me3 modification. Disruption of the gene encoding Sgf29 delays accumulation of H3K9Ac and abrogates H3K4me3-directed H3Ac. Either loss or overexpression of Sgf29 confers developmental resistance to TSA. Our results demonstrate that rapid acetylation of H3K4me3 histones regulates developmental sensitivity to TSA. Levels of H3K4me3 or Sgf29 will provide useful biomarkers for sensitivity to this class of chemotherapeutic drug.
Highlights
Specific post-translational modifications of histone proteins are associated with gene expression
We identify a Dictyostelium homologue of Sgf29, a reader of H3K4me2/3 found in the Gcn5 HAT complex from yeast to humans, and show that disruption of the gene leads to loss of rapid acetylation of H3K4me3 histones and confers trichostatin A (TSA) resistance
Dictyostelium development is inhibited by exposure to TSA in the early stages of development In Dictyostelium the developmental cycle is triggered by starvation, at which point the cells exit the proliferative cell cycle, and individual amoebae aggregate together to form a multicellular structure
Summary
Specific post-translational modifications of histone proteins are associated with gene expression. Methylation of histone H3 on lysine 4 (H3K4) is a hallmark of genes accessible for transcription from yeast to humans, with the lysine modified by the addition of up to three methyl groups Within active genes, these modifications are region-specific. H3K9 and H3K14 at the TSS region of actively transcribed genes [3] are substrates for members of the Gcn N-acetyltransferases (GNATs), MYST (Morf, Ybf, Sas and Tip60) and p300/CBP acetyltransferases [4,5,6] These histone modifications can be removed by lysine demethylases (KDMs) and deacetylases (KDACs) to allow dynamic turnover and resetting of modifications associated with a particular gene, without histone replacement
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