Histone proteins HDACs

Histone Deacetylases (HDACs) catalyze the removal of the acetyl groups from lysines (see Fig. 1). Together with the HATs they are responsible for maintaining the level of histone acetylation throughout the genome. The family of HDAC proteins has been divided into four classes based on phylogenetic analysis and sequence comparison. HDACs of the classes I and II share the same Zn2+-based reaction and are evolutionary related. Class IV HDACs also possess a Zn2+-based reaction... 

Gui CV, Ngo L, Xu WS, Richon VM, Marks PA. (2004) Histone deacetylase (HDAC) inhibitor activation of p21WAFl involves changes in promoter-associated proteins, including HDACl. Proc Natl Acad Sci USA 101 1241-1246. 

HATs catalyze the post-translational acetylation of amino-terminal lysine tails of core histones, which results in disruption of the repressive chromatin folding and an increased DNA accessibility to regulatory proteins. The level of histone acetylation is highly controlled and balanced by the activity of histone deacetylases (HDACs), the opponents of HATs. Generally, acetylation is correlated with activation and deacetylation with repression of gene expression. Therefore, the dynamic equilibrium of these proteins represents a key mechanism of gene regulation. 

In the absence of ligand, some nuclear hormone receptors associate with co-repressors, namely, SMRT (silencing mediator of retinoic acid and thyroid hormone receptors) and N-CoR (nuclear receptor co-repressor). Both, SMRT and N-CoR, recruit coregulatory protein SINS and histone deacetylases (HDACs) to form a large co-repressor complex that contains histone deacetylase activity, implicating histone deacetylation in transcriptional repression [52,53]. 

The family of HDAC enzymes has been named after their first substrate identified, i.e., the nuclear histone proteins. Histone proteins (H2A, H2B, H3 and H4) form an octamer complex, around which the DNA helix is wrapped in order to establish a condensed chromatin structure. The acetylation status of histones is in a dynamic equilibrium governed by histone acetyl transferases (HATs), which acetylate and HDACs which are responsible for the deacetylation of histone tails (Fig. 1). Inhibition of the HDAC enzyme promotes the acetylation of nucleosome histone tails, favoring a more transcriptionally competent chromatin structure, which in turn leads to altered expression of genes involved in cellular processes such as cell prohferation, apoptosis and differentiation. Inhibition of HDAC activity results in the activation of only a limited set of pre-programmed genes microarray experiments have shown that 2% of all genes are activated by structmally different HDAC inhibitors [1-5]. In recent years, a growing number of additional nonhistone HDAC substrates have been identified, which will be discussed in more detail below. 

The histone deacetylases are found in large protein complexes, often together with repressive transcription factors. By this token, interactions of the repressive heterodi-meric transcription factor Mad-Max and a complex with the histone deacetylase HDAC I and the mSinSA protein have been demonstrated. A complex of HDAC I and the nuclear receptor-corepressor (see chapter 4) binds to unliganded nuclear receptors and is believed to exercise a repressive effect. A further example is the tumor suppressor protein pRb (see chapters 13,14), which can occur as a transcription repressor in the hypo-phosphorylated form and transcriptionally activating in the hyperphosphorylated form. The repressive form of the pRb protein recruits the histone deacetylase HDAC 1 to the DNA and thereby initiates an active repression of the gene (see 13.3.2). 

The DNMTs at least partially account for the interaction of DNA methylation with histone modification as these enzymes are able to directly recruit histone deacetylases (HDACs) and this is achieved by binding methylated C ( etQ binding proteins such as MeCP2, MBD1, MBD2, and MBD3 (detailed reviews in Refs. 24 and 25). 

Histone deacetylases (HDACs), histone acetyltransferases (HMTs), histone demethylases (HDMTs), protein arginine methyltransterases (PRMTs), histone arginine demethylases (HADs), and DNA methyltransferases (DNMTs). 

Figure 2 A model for RAR/RXR acting in concert with coactivator or corepressor complex for gene activation or silencing. In the presence of ligands (+RA), the holo-receptor pair binds to the RA response element (RARE) and recruits coactivator complex, which encodes histone acetyl transferase (HAT) activity. HAT acetylates histone proteins, opens up the chromatin, and allows the transcription machinery to act on the promoter for active gene transcription. In the absence of ligands (—RA), the apo-receptor pair binds to the RARE and recruits corepressor that encodes histone deacetylase (HDAC) activity, inducing histone deacetylation, chromatin condensation, and gene silencing.

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