Histone deacetylase Modifications

Histone Acetylation. Figure 1 Histone acetylation is a posttranslational modification of lysine residues of histones. This modification is catalyzed by histone actyl transferases (HATs), which transfer an acetyl group (yellow) from acetyl-Coenzyme A onto the E-amino group of the lysine residue. Histone deacetylation is catalyzed by histone deacetylases (HDACs), which hydrolyze the lysine bound acetyl group. HDAC inhibitors like Trichostatin A (TSA) are known to inhibit the deacetylation reaction in vivo and in vitro. 

The exact role of individual histone acetylations will have to be determined in the context of other modifications and the number of lysine residues effected. However, the general importance of histone acetylation as a regulator for chromatin activity is undisputed. This leads to the intriguing possibility to develop drugs that target histone acetylation for therapeutic purposes. The primary targets for drug development are the histone acetyl transferases (HATs) and the histone deacetylases (HDACs) which introduce and remove histone acetylations [2, 3]. 

One of the most-studied covalent modifications is the acetylation of the lysine residues of histone tails. The acetylation state of lysines of nucleosomal histones modulates chromatin structure and regulates gene transcriptional activity. The balance of lysine acetylation is controlled by the antagonistic action of two enzyme families histone deacetylases (HDACs) and histone acetyltransferases (HATs). In humans there are essentially three main HDAC subclasses [6]. 

Peterson CL, Laniel MA (2004) Histones and histone modifications. Curr Biol 14 R546-R551 Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS (2001) Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem 276 36734-36741... 

Lee, C.W, Kang, J.S., Lee, K. et al. (2007) Modification of cap group in d-lactam-based histone deacetylase (HDAC) inhibitors. Bioorganic ei Medicinal Chemistry Letters, 17, 6234-6237. 

Enzymes that cleave off modifications may be assayed by measuring the formation of either the protein or a protein-mimicking substrate or the small molecule produd or byproducts (like acetate for histone deacetylases, or formaldehyde or hydrogen peroxide for histone demethylases). Transferases may generally be screened by measuring the conversion of the cosubstrate or quantitatin the formation of the... 

DNA methylation may directly decrease the binding affinity of certain transcription factors to DNA [38]. Additionally, methylated CpG sites recruit MBD proteins, which in turn leads to transcriptional repression [39]. siRNA-mediated knockdown of MBD proteins leads to a re-expression of silenced tumor suppressor protein candidates [40]. DNA methylation and histone modification are dependent on each other [41, 42] and from this interplay a synergy in derepression (e.g. between histone deacetylase and DNMT inhibitors) can be observed [43—45] (see also below). 

Recent studies have shown that the acetylation or deacetylation of the histones of the nucleosome plays an important role in the regulation of transcriptional activity. Acetylation of the histones (review Hassig and Schreiber, 1997) is a postranslational modification which is usually performed on lysine residues at the N-terminus and requires specific enzymes,the histone acetyl transferases (HATs). Removal of the acetyl group also requires specific enzymes, the histone deacetylases (HDAC). Most importantly, the acetylation of histones is accompanied by a loss of postive charges which is thought to have a profound influence on the nucleosome structure and on the strength of DNA-binding. 

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). 

Just as in prokaryotes, some changes in a cell s environment lead to the repression of genes that had been active. The modification of histone tails again plays an important role. However, in repression, a key reaction appears to be the deacetylation of acetylated lysine, catalyzed by specific histone deacetylase enzymes. 

Transition of active to inactive states of chromatin (and vice versa) is controlled by epigentic modifications including acteylation of N-terminal Lys residues of histones H3 and H4, methylation of Lys9 of H3 and methylation of CpC sequences. CpC methylation induces binding of Methy-C-binding proteins (MeCP and MDB proteins) which in turn leads to recruitment of histone deacetylase activity (HDAC) establishing a repressed state of the chromatin. 

Zhao X et al (2005) Regulation of MEF2 by histone deacetylase 4- and SIRT1 deacetylase-mediated lysine modifications. Mol Cell Biol 25(19) 8456-8464... 

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