Figure 1. Chromatin remodeling. A. Picture of a nucleosome shoving a DNA strand wrapped around a histone octamer composed of two copies each of the histones H2A, H2B, H3 and H4. The amino (N) termini of the histones face outward from the nucleosome complex. B. … Histone acetylation Acetylation of histone lysine residues reduces the electrostatic interaction between histone Inhibitors,research,lifescience,medical proteins and DNA, which relaxes chromatin structure and improves access of transcriptional regulators to DNA (Figure 1).6 Genome-wide studies indicate that high levels

of histone acetylation in gene promoter regions are generally associated with higher gene activity, while low levels of acetylation correlating Inhibitors,research,lifescience,medical with reduced gene activity.9 Most genome-wide studies of histone acetylation have focused on acetylation of the N-terminal lysine residues in histones H3 and H4, but histone acetylation can occur on other histone proteins as well as in their globular

domains. Histone acetylation is a dynamic process, controlled by specific enzymes which either add or remove the acetyl mark. There are over a dozen known histone acetyltransferases (HATs) which catalyze the addition of Inhibitors,research,lifescience,medical acetyl groups onto lysine residues of histones with varying degrees of specificity. Many HATs can also acetylate nonhistone proteins such as transcription factors (eg, p53), and some transcription factors (eg, ATF2 [activating transcription factor 2], CLOCK) even possess intrinsic HAT activity that contributes to gene activation.10,11 Histone deacetylases Inhibitors,research,lifescience,medical (HDACs), which remove acetyl groups from histones, are divided into

Inhibitors,research,lifescience,medical four classes. Class I HDACs (eg, HDAC1, 2, 3, and 8) are ubiquitously expressed and check details likely mediate the majority of deacetylase activity within cells. Class II HDACs (eg, HDAC4, 5, 7, 9, 10) are only expressed in specific tissues such as heart and brain and are much larger enzymes that also contain an N-terminal regulatory domain that enables them to be shuttled in and out of the nucleus in a neural activitydependent manner.12 While Class II HDACs can deacetylate histones, they are much less efficient enzymes than Class I HDACs, and Thymidine kinase may also deacetylate other cellular substrates.13,14 There is currently one Class IV HDAC, HDAC11, and it has characteristics of both Class I and Class II enzymes.15 Class III IIDACs (also referred to as sirtuins) are mechanistically distinct from the other HDACs, and have been implicated in the regulation of lifespan and metabolism.16 The individual functions of each IIDAC remain an active topic of investigation.