Acetylation of histones

Beside coactivators so-called corepressors exist that are bound to transcription factors such as nuclear receptors and inhibit the initiation of transcription. These factors include the nuclear receptor corepressor (NCoR) and the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT), which interact with nuclear receptors and serve as platforms for complexes containing histone deacetylases (HDACs). These enzymes cause the reversal of histone acetylation of histones leading to a tightening of chromatin and enhancing its inaccessibility for RNA polymerase containing complexes. 

The core unit of the chromatin, the nucleosome, consists of histones arranged as an octamer consisting of a (H3/ H4)2-tetramer complexed with two histone H2A/H2B dimers. Accessibility to DNA-binding proteins (for replication, repair, or transcription) is achieved by posttranslational modifications of the amino-termini of the histones, the histone tails phosphorylation, acetylation, methylation, ubiquitination, and sumoyla-tion. Especially acetylation of histone tails has been linked to transcriptional activation, leading to weakened interaction of the core complexes with DNA and subsequently to decondensation of chromatin. In contrast, deacetylation leads to transcriptional repression. As mentioned above, transcriptional coactivators either possess HAT activity or recruit HATs. HDACs in turn act as corepressors. 

Acetylation of histones H3 and H4 is associated with the activation or inactivation of gene transcription (Chapter 37). 

Sterner DE, Berger SL Acetylation of histones and transcription-related factors. Microbiol Mol Biol Rev 2000 64 435. 

Two types of modifications occur (see Figs. 1 and 2) (a) amino-terminal acetylation of histones HI, H2A, and H4 with the formation of a-acetylserine. This modification occurs in the cytoplasm before the histones are transported to the nucleus (Liew et al., 1970), and is apparently an irreversible modification (b) the formation of N8-... 

Figure 2. Histone chaperones facilitate favorable chromatin dynamics during transcriptional activation Transcriptional competence of chromatin template is achieved by die replacement of histone variants and finally removal of histones. Histone chaperone may help in bodi die process in a replication independent manner. Acetylation of histone and also die chaperone may assist in diis process. Recent evidence suggest that NPMl may participate in these events globally or gene specific manner. (See Colour Plate 11.)...

Reversible acetylation of histone and nonhistone proteins play key role in maintaining cellular homeostasis. In this following section we shall discuss about the physiological significances of acetylation and deacetylation of different classes of nonhistone proteins. 

Figure 4. Histone modification cross-talk between phosphorylation of histone H3 (SIO) and acetylation of histone H3 (K14) or methylation of histone H3 (K9). Histone H3 phoshorylation at SIO can enhance acetylation of histone H3 at K14 (Cheung et at, 2000), (Lo et at, 2000). (b) Histone H3 phoshorylation at SIO abolish acetylation of histone H3 at K9 (Edmondson et at, 2002). (c) Histone H3 phoshorylation at SIO inhibits methylation of histone H3 at K9 (Rea et at, 2000). (d) methylation of histone H3 at K9 interferes with phosphorylation of histone H3 at SIO. Phosphorylation is represented by the blue flag, acetylation is represented by the black flag, and methylation represented by the green flag...

Shi Y, Lan L, Matson C, Mulhgan P, Whetstine JR, Cole PA, Casero RA, Shi Y (2004) Histone demethylation mediated by the nuclear amine oxidase homolog LSDl. Cell 119 941-953 Shilatifard A (2006) Chromatin Modifications by Methylation and Ubiquitination Implications in the Regulation of Gene Expression. Annu Rev Biochem 75 243-269 Sterner DE, Berger SL (2000) Acetylation of histones and transcription-related factors. Microbiol. Mol Biol Rev 64 435-459... 

Belli SI (2000) Chromatin remodelling during life cycle of trypanosomatids. Int J Parasitol 30 679-687 Berger SL, Sterner DE (2000) Acetylation of histones and transcription-related factors, microbiology and molecular biology reviews, June 435 59... 

The results obtained from the histone acetylation and phosphorylation studies suggest that cyclo(Trp-Trp) and cyclo(Pro-Trp) induce differential gene expression through different signal transduction pathways. Cyclo(Trp-Trp) induced the highest level of acetylation of histones whereas cyclo(Phe-Pro) induced high levels of phosphorylation of histones." ... 

Local chromatin-modifying activities Acetylation of histones increases gene expression (many genes) Methylation of DNA silences genes in genetic imprinting (Prader-Willi and Angelman syndromes)... 

Lea MA, Randolph VM, Patel M. (1999) Increased acetylation of histones induced by diallyl disulfide and structurally related molecules. Int J Oncol 15 347-352. 

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]. 

---