Acetylation histone

Histone acetylation is a reversible amidation reaction involving defined e-amino groups of lysine residues (see Fig. 6) at the N-terminal tails of core histones. The highly dynamic equilibrium between the acetylated and non-acetylated states of lysine is maintained by two enzymatic groups, referred to as histone acetyltransferases (HATs) and histone deacetylases (HDACs). 

The correlation between histone acetylation and eukaryotic transcription were recognized many years ago [128,129]. However, it has not been until very recently, with the discovery that both HATs [130-133] and HDACs [134-138] are an integral part of the basal transcriptional machinery, that the molecular link for this correlation was established. This discovery has rekindled interest in this post-translational histone modification with implications ranging from basic chromatin research to applied medical investigations. Indeed, histone acetylation has been linked to cancer [139-144] and certain types of HDAC inhibitors are already being used to treat certain forms of cancer [145]. 

Beyond the modulation of eukaryotic gene expression, histone acetylation has also been functionally linked to histone deposition during DNA replication (see Ref. [146] for a review) and in the displacement/replacement of histones by protamines during spermiogenesis in those vertebrate (see Ref. [147] for a review) and invertebrate organisms [148] whose sperm chromatin consists of protamines [118]. 

Despite all these well-established functional implications, the structural involvement of this chemical modification in the chromatin changes involved in these processes has remained largely elusive [29]. 

The global effects of acetylation have long been recognized [153] and studied in the chromatin field [126,127,154—156]. However, whether such effects are the 

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More subtle modes of action are also possible since the response to hormone receptor binding is complex and could be affected by chemical interference with receptor-related proteins, DNA methylation or histone acetylation. Dioxin (TCDD), for example, reduces the ability of the oestrogen-receptor complex to bind to the oestrogen response element of DNA, reducing gene transcription. ... 

Clock gene and transcription factor with histone acetyl-transferase (HAT) activity that (in complex with BMAL1) constitutes a positive limb of molecular circadian oscillators. 

Cytokines such as TNFa and IL-1 3, acting via NF-kB, can induce histone acetylation in both a time- and concentration-dependent manner. Upon DNA binding, NF-kB recruits transcriptional coactivators such as CREB binding protein (CBP) and p300/CBP-associated factor (PCAF). 

Clayton AL, Hazzalin CA, Mahadevan LC (2006) Enhanced histone acetylation and transcription a dynamic perspective. Mol Cell 23 289-96... 

Histone acetylation is a reversible and covalent modification of histone proteins introduced at the e-amino groups of lysine residues. Histones and DNA form a complex - chromatin - which condenses DNA and controls gene activity. Current models interpret histone acetylation as a means to regulate chromatin activity. 

A model called histone code theory includes more aspects of chromatin regulation which have been identified. The histone code theory predicts that histone acetylation and other posttranslational histone modifications serve as binding sites for regulatory proteins which mediate processes like gene transcription upon recruitment (see Fig. 2b) [3]. In this context histone modifications can be understood as... 

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. 

An important aspect of the histone code theory is that some modifications can be passed on during cell division. As a result histone modification patterns including histone acetylation serve as a means to store inheritable traits of an organism which are not DNA encoded. This kind of information is generally termed epigenetic information. 

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]. 

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... 

TBP-RNA polymerase) (ii) they are potent histone acetyl transferases inducing chromatin remodeling (loosening). 

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. 

Histone Acetylation Histone Deacetylases Histone Methylation Histone Phosphorylation Histone Tails Hrv... 

Grunstein M Histone acetylation in chromatin structure and transcription. Nature 1997 389 349. 

Review] [67 refs]. Clin Diagn Lab Immunol 7 719-723 Bodnar RJ (2007) Endogenous opiates and behavior 2006. Peptides 28 2435-2513 Boekhoudt GH, Guo Z, Beresford GW, Boss JM (2003) Communication between NF-kappa B and Spl controls histone acetylation within the proximal promoter of the monocyte chemoattractant protein 1 gene. J Immunol 170 4139-4147... 

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