Histone modifications acetylation

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... 

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. 

Strahl BD, Allis CD (2000) The language of covalent histone modifications. Nature 403 41-45 Suto RK, Clarkson MJ, Tremethick DJ, Luger K (2000) Crystal structure of a nucleosome core particle containing the variant histone H2A.Z. Nature Struct. Biol. 7 1121-1124 Swaminathan J, Baxter EM, Corces VG (2005) The role of histone H2Av variant replacement and histone H4 acetylation in the establishment of Drosophila heterochromatin. Genes Dev 19 65-76... 

Figure 3. Histone modification cross-talk between histone H2A phosphorylation on T119 and another histones methylation or acetylation in nhk-1 mutants (a) Histone H3 (K14) and (b) Histone H4 (K5) are not acetylated in the nhk-1 mutant, (c) Histone H4 (K12) is acetylated in the nhk-1 mutant (Ivanovska et al. 2005). Phosphorylation is represented by the blue flag, and acetylation is represented by the black flag...

We have discussed phosphorylation of histone H3, which has been studied in many organisms. Phosphorylation of histone H3 (SIO) has two opposite main functions. One is necessary to initiate chromosome condensation during mitosis and meiosis, while the other is transcriptional activation. Current evidence shows that a combination of phosphorylation of H3 (SIO) and methylation of H3 (K9) or acetylation H3 (K9, K14) play important roles in these phenomena including cell cycle related chromosome dynamics and transcriptional activation. These results suggest that a combination of different histone modifications excute different biological outcomes. 

In contrast to simple charge neutralization effects, the effects on protein recog-nition/recruitment are collectively referred to as the histone code . This hypothesis predicts that specific patterns of histone tail acetylations and other modifications serve as epigenetic marks for distinct sets of regulatory proteins to differentially modulate chromatin structure and function (Strahl and Allis, 2000 Turner, 2000 Jenuwein and Allis, 2001). Indeed, several recent findings have demonstrated that histone acetylation creates a signal for the binding of a bromodomain which has... 

Strahl BD, Allis CD (2000) The language of covalent histone modifications. Nature 403 41-45 Suganuma T, Kawabata M, Ohshima T, Ikeda MA (2002) Growth suppression of human carcinoma cells by reintroduction of the p300 coactivator. Proc Natl Acad Sci USA 99 13073-13078 Timmermann S, Lehrmann H, Polesskaya A, Harel-Bellan A (2001) Histone acetylation and disease. Cell Mol Life Sci 58 728-736... 

The phenylselenocysteine has also been used successfully to chemically append analogues of methyl- or acetyl-lysine, important histone modifications that can contribute to chromatin structure and accessibility of transcriptional machinery in eukaryotes. By introducing phenylselenocysteine into the Xenopus histone H3, both acetyl-lysine and mono-, di-, and trimethyl-lysine analogues were appended to the purified unnatural amino acid-containing FI 3 protein (Figure 10). " Additionally, the H3 protein with a modification mimicking acetylation of lysine 9 can be deactylated by a histone deacetylation complex and is also a substrate for phosphorylation by Aurora B kinase. Such purified and chemically labeled histones are likely functional in nucleosomes, and preparation of specifically modified histones for comprehensive analysis of chromatin structure and accessibility is particularly suited to this chemical labeling technique. 

Fig. 1. Core histone modifications. Human histone N-terminal and in some cases C-terminal amino acid sequences are shown. The modifications include methylation (M), acetylation (Ac), phosphorylation (P), ubiquitination (U), and ADP ribosylation (step ladder). The sites of trypsin digestion of histones in nucleosomes are indicated (T).

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]. 

Experimental results regarding the role of the histone tails indicate that these histone domains play a critical role in chromatin folding [358,365]. Removal as well as the modification (acetylation) of the lysine amino acids within these regions produces an imbalance of the electrostatic interactions, which results in a hierarchically impaired folding ability (H3/H4-H2A/H2B>H3/H4>H2A/H2B) of the chromatin fiber [358,366-369]. Therefore, sources of histone tail variability (histone variants and post-translational modifications other than lysine acetylation) are also likely to alter the extent of folding of chromatin. 

The structure of the acetylated nucleosome core particle The early characterization of acetylated nucleosomes suggested that this histone modification imparted some important structural changes at the level of the nucleosome core particle. It was found that the flanking DNA regions at the entry... 

Fig. 1. Histone modifications on the nucleosome core particle. The nucleosome core particle showing 6 of the 8 core histone N-terminal tail domains and 2 C-terminal tails. Sites of post-translational modification are indicated by coloured symbols that are defined in the key (lower left) acK = acetyl lysine, meR = methyl arginine, mcK = methyl lysine, PS = phosphoryl serine, and uK = ubiquitinated lysine. Residue numbers are shown for each modification. Note that H3 lysine 9 can be either acetylated or methylated. The C-terminal tail domains of one H2A molecule and one H2B molecule are shown (dashed lines) with sites of ubiquitination at H2A lysine 119 (most common in mammals) and H2B lysine 123 (most common in yeast). Modifications are shown on only one of the two copies of histones H3 and H4 and only one tail is shown for H2A and H2B. Sites marked by green arrows are susceptible to cutting by trypsin in intact nucleosomes. Note that the cartoon is a compendium of data from various organisms, some of which may lack particular modifications e.g., there is no H3meK9 in S. cerevisiae. (From Ref [7].)...

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