Lysine Acetylation of Histones

An enzyme activity ascribed to many coactivators, which transfers acetyl groups to lysine residues of histone tails of the nucleosomes and thereby facilitate their disruption and the opening of the chromatin. 

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. 

Enzyme activity ascribed to corepressors, which is the removal of acetyl groups from lysine residues of histone tails. Thereby the assembly of nucleosomes is maintained, which leads to a dense, transcriptional inactive chromatin structure. 

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]. 

Histone acetyltransferases (HATs) are enzymes that acetylate specific lysine residues in histones through the transfer of an acetyl group from an acetyl-coenzymeA (AcCoA) molecule, causing profound effects on chromatin structure and assembly as well as gene transcription. HATs are found in most, if not all, eukaryotic organisms as multiprotein complexes, some HAT catalytic subunits even being shared between various complexes that display different substrate specificities based on their subunit composition [12]. Despite their name, HATs do not restrict themselves to the acetylation of histones, since these enzymes have also been shown to act on nonhistone proteins, broadening their scope of action [13]. 

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. 

Acetylation of the lysine residues of histones H3 and H4 was one of the first modifications of chromatin to be described (Fig. 1) (14). It is associated with the establishment of an open chromatin state that is active transcriptionally. This modification contrasts with hypoacetylation, which is associated with a compacted chromatin structure that is inaccessible to transcription machinery. The majority of all lysine residues of the N-terminal tails of histones H3, H4, H2A, and H2B have the ability to be... 

Differences in the acetylation state of histones between the male and female pro-nuclei may also contribute to the differences in the transcriptional activity of the two pronuclei (Adenot et al., 1997). Acetylation of histones is now widely recognized as a posttranslational modification that is highly correlated with the presence of transcriptionally permissive chromatin (O Neill and Turner, 1996 and references therein). The acetylation of the amino terminal residues in the histones is catalyzed in a specific sequence. For histone H4 in humans, the sequence is lysine 16, then lysine 8 and/or 12, and then lysine 5 (Turner et al., 1989) fully acetylated histone H4 is acetylated on lysines, 5, 8,12, and 16. 

M. Esteller, Loss of acetylated lysine 16 and trimethylated lysine 20 of histone H4 is a common hallmark of human cancer, Nat. Genet. 2005, 37, 391-400. 

Another way in which regions of DNA can be transcriptionally activated is by acetylation of specific lysine residues in the N-terminal tails (Figure 28.28) of histones in the nucleosomal core. A number of proteins recruited to the initiation complex by transcriptional activators and TATA binding associated factors TAFs have histone acetylase activity. Acetylation of histones in promoter nucleosomes may help loosen thechromatin structure in these regions. 

Histone deacetylases (HDAC) are a class of enzymes that catalyze the removal of acetyl groups from the A -acetylated lysine residues of histone. Histones are the major protein components of chromatin, act as spools around which DNA winds, and play an important role in gene regulation. As certain tumors overexpress HDAC, inhibition of HDAC results in accumulation of acetylated histones, thereby causing cell cycle arrest and apoptosis. 

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