Genes Are Often Sheltered from the Global Histone Hyperacetylation Induced by HDAC Inhibitors

John Halsall,Laura P O'Neill,Bryan M Turner,Karl P Nightingale,Vibhor Gupta

doi:10.1371/journal.pone.0033453

Abstract

Histone deacetylase inhibitors (HDACi) are increasingly used as therapeutic agents, but the mechanisms by which they alter cell behaviour remain unclear. Here we use microarray expression analysis to show that only a small proportion of genes (∼9%) have altered transcript levels after treating HL60 cells with different HDACi (valproic acid, Trichostatin A, suberoylanilide hydroxamic acid). Different gene populations respond to each inhibitor, with as many genes down- as up-regulated. Surprisingly, HDACi rarely induced increased histone acetylation at gene promoters, with most genes examined showing minimal change, irrespective of whether genes were up- or down-regulated. Many genes seem to be sheltered from the global histone hyperacetyation induced by HDACi.

Highlights

The post-translational modification of core histones plays a central role in epigenetic gene regulation [1]
We have shown previously that HL60 cells exposed to histone deacetylase (HDAC) inhibitor (HDACi) exhibit a rapid increase in histone acetylation, which plateaus after,8 hours of treatment [15]
Cell cycle response to HDACi We characterised the cellular response to three inhibitors at concentrations that induced similar levels of global histone hyperacetylation [22]

Summary

Introduction

The post-translational modification of core histones plays a central role in epigenetic gene regulation [1]. Salts of short chain fatty acids (e.g. butyric, propionic, acids) occur at millimolar concentrations in the mammalian large intestine, and have been known for many years to induce histone hyper-acetylation in cultured cells [6]. They do this by inhibiting members of the histone deacetylase (HDAC) family, enzymes which together with histone acetyl transferases, maintain the dynamic distribution of histone acetylation across the genome [2]. This, and the recognition that HDACi induce global changes in other histone modifications [15] and impact on the acetylation of non-histone proteins [16], suggest that the mechanisms that underpin gene responses to HDACi are complex [17]

Methods

Results

Conclusion