Cells adapt to the epigenomic disruption caused by histone deacetylase inhibitors through a coordinated, chromatin-mediated transcriptional response

Background: Histone deacetylase inhibitors (HDACi) induce genome-wide hyperacetylation of chromatin, a process that, surprisingly, is well tolerated by most eukaryotic cells. The mechanisms that maintain this tolerance remain poorly understood. In this study, we investigate the early transcriptional and epigenomic responses of human lymphoblastoid cells to two clinically relevant HDACi, valproic acid and suberoylanilide hydroxamic acid (Vorinostat).
Results: Using high-density microarrays, we analyzed dynamic changes in transcript levels during the first 2 hours of HDACi exposure. A consistent transcriptional response was observed for both inhibitors across various concentrations. Notably, genes encoding components of all major lysine acetyltransferase (KAT) complexes were downregulated, along with genes critical for lymphoid growth and phenotype maintenance. In contrast, upregulated gene clusters were enriched in transcriptional regulators, as well as genes associated with development and phenotypic transitions. In untreated cells, HDACi-responsive genes—whether up- or downregulated—were housed GSK503 within regions of highly acetylated chromatin, which remained largely unchanged upon HDACi exposure. However, HDACi induced a robust increase in H3K27me3 at transcription start sites, irrespective of the transcriptional direction of the affected genes. Functional inhibition of the H3K27 methyltransferases EZH1 and EZH2 altered the transcriptional response to HDACi, underscoring the significance of H3K27 methylation in mediating this response.
Conclusions: These findings suggest that the transcriptional changes elicited by HDACi represent an adaptive cellular response that supports survival by mitigating protein hyperacetylation, decelerating growth, and rebalancing gene expression patterns. This response is orchestrated by a tightly regulated increase in H3K27me3 at transcription start sites, which appears to play a pivotal role in mediating gene-specific transcriptional changes. In contrast, histone acetylation at the lysine residues analyzed does not appear to directly drive transcriptional alterations. Instead, it may provide a stable chromatin environment that facilitates transcriptional changes driven by other factors, potentially including acetylated non-histone proteins.