Abstract
BackgroundThe genome-wide hyperacetylation of chromatin caused by histone deacetylase inhibitors (HDACi) is surprisingly well tolerated by most eukaryotic cells. The homeostatic mechanisms that underlie this tolerance are unknown. Here we identify the transcriptional and epigenomic changes that constitute the earliest response of human lymphoblastoid cells to two HDACi, valproic acid and suberoylanilide hydroxamic acid (Vorinostat), both in widespread clinical use.ResultsDynamic changes in transcript levels over the first 2 h of exposure to HDACi were assayed on High Density microarrays. There was a consistent response to the two different inhibitors at several concentrations. Strikingly, components of all known lysine acetyltransferase (KAT) complexes were down-regulated, as were genes required for growth and maintenance of the lymphoid phenotype. Up-regulated gene clusters were enriched in regulators of transcription, development and phenotypic change. In untreated cells, HDACi-responsive genes, whether up- or down-regulated, were packaged in highly acetylated chromatin. This was essentially unaffected by HDACi. In contrast, HDACi induced a strong increase in H3K27me3 at transcription start sites, irrespective of their transcriptional response. Inhibition of the H3K27 methylating enzymes, EZH1/2, altered the transcriptional response to HDACi, confirming the functional significance of H3K27 methylation for specific genes.ConclusionsWe propose that the observed transcriptional changes constitute an inbuilt adaptive response to HDACi that promotes cell survival by minimising protein hyperacetylation, slowing growth and re-balancing patterns of gene expression. The transcriptional response to HDACi is mediated by a precisely timed increase in H3K27me3 at transcription start sites. In contrast, histone acetylation, at least at the three lysine residues tested, seems to play no direct role. Instead, it may provide a stable chromatin environment that allows transcriptional change to be induced by other factors, possibly acetylated non-histone proteins.Electronic supplementary materialThe online version of this article (doi:10.1186/s13072-015-0021-9) contains supplementary material, which is available to authorized users.
Highlights
The genome-wide hyperacetylation of chromatin caused by histone deacetylase inhibitors (HDACi) is surprisingly well tolerated by most eukaryotic cells
Cells respond to HDACi with a transcription based, adaptive response that allows them to survive in the presence of the inhibitor
The response includes the universal down-regulation of known lysine acetyltransferase (KAT) complex components, a change that will diminish and eventually eliminate protein hyperacetylation caused by histone deacetylases (HDACs) inhibition, and the up-regulation of developmental regulators that adjust transcription to accommodate inhibitor-induced epigenomic changes
Summary
The genome-wide hyperacetylation of chromatin caused by histone deacetylase inhibitors (HDACi) is surprisingly well tolerated by most eukaryotic cells. Like other post-translational histone modifications, acetylation rarely acts in isolation, but as part of a combination of different modifications, usually along the histone N-terminal tails, that collectively regulate chromatin function [10,11,12]. There is a long-standing connection between relatively high levels of overall histone acetylation and transcriptional activity [16,17,18] This association is supported by more recent epigenomic studies [19,20,21,22,23,24], and by experiments on the functional consequences of acetylation of specific histone lysines. H3K9 acetylation is consistently enhanced at gene promoter regions [28, 29], while H3K27 acetylation protects this residue from methylation by the Polycomb silencing Complex PRC2 and consequent longterm suppression of transcription [30, 31]
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