Roles of histone deacetylases in epigenetic regulation: emerging paradigms from studies with inhibitors

Acetylation of the lysine ε-amino group, first discovered on histones, is a dynamic posttranslational modification (PTM) regulated by the opposing activities of lysine acetyltransferases (KATs) and histone deacetylases (HDACs). Histone acetylation is a modulator of chromatin structure involved in DNA replication, DNA repair, heterochromatin silencing and gene transcription [1,2]. Hyperacetylation usually marks transcriptionally active genes, as it contributes to the decondensed chromatin state and maintains the unfolded structure of the transcribed nucleosome [2-6]. Moreover, specific acetylated sites on core histones are read by bromodomain modules found in proteins, and sometimes in KATs, which are components of chromatin-remodeling complexes involved in transcriptional activation [7]. Conversely, HDACs are found in corepressor complexes and, by removing acetyl groups from histones, induce the formation of a compacted, transcriptionally repressed chromatin structure. As discussed below, however, this model reflects quite an oversimplification of the role of HDACs in transcription regulation.Many nonhistone proteins (transcription factors, regulators of DNA repair, recombination and replication, chaperones, viral proteins and others) are also subject to acetylation [8-10]. Investigators in a recent study used high-resolution mass spectrometry to identify 3,600 acetylation sites in 1,750 human proteins and showed that lysine acetylation is implicated in the regulation of nearly all nuclear functions and many cytoplasmic processes [11]. Furthermore, acetylation is regulated by and/or regulates other PTMs. Through either recruitment or occlusion of binding proteins, PTMs may lead to or prevent a secondary PTM on histones and nonhistone proteins [12,13]. In particular, histone H3 phosphorylation on serine 10 or 28, rapid and transient PTMs in response to the stimulation of signaling pathways such as the mitogen-activated protein kinase (MAPK) pathways, are associated w