HDACs are divided into four distinct classes based on their homology to the yeast proteins rpd3 (Class I), hda1 (Class II), sir2, (Class III), and a unique Class IV deacetylase that shares features with both rpd3 and hda1. In mammals, Class I HDACs (HDAC1, 2, 3, 8) are ubiquitously expressed and are far more active against histone substrates than Class II HDACs (HDAC4, 5, 6, 7, 9) [39]. Both Class I and Class II HDACs share a conserved catalytic domain, which requires zinc for activity, but Class II HDACs are much larger proteins which contain an N-terminal regulatory region that controls subcellular localization and interaction partners [40]. Class III HDACs, the sirtuins (SIRT1-7), are distinct from the other classes structurally and mechanistically; they require NAD+ as a cofactor instead of zinc to catalyze histone deacetylation (Figure 1) [41]. HDACs are highly regulated through post-translational modifications that control their activity, subcellular localization, or stability. The catalytic activity of Class I HDACs is regulated by phosphorylation by casein kinase II for HDACs 1–3 [42], and by PKA for HDAC8 [43, 44]. Class
