Methylation histone

Histone methylation was first reported in 1964 [118], Core histones H2B, H3, and H4 are modified by methylation (Fig. 1). H3 and H4 are modified at lysines and arginines located primarily in the N-terminal tail. Histone methylation does change the charge of the protein at physiological pH. However, methylation does increase the hydrophobicity of the lysine residue and reduces its ability to form hydrogen bonds [119]. The sites of methylation (Lys-20 in H4 and Lys-27 in H3) are positioned at the boundary between the very basic N-terminal tail domain and the more hydrophobic sequence of the remainder of the molecule. Lys-20 of histone H4 is also in the basic region that binds to nucleosomal DNA [120]. Methylation at these sites may alter nucleosome structure [121,122]. 

In different organs of the rat [128], Ehrlich ascites tumor cells [144], trout testis [127], calf thymus [145], and carp testis [146], H4 is modified mainly as the N -dimethyllysine, while H3 is modified as N -monomethyllysine, N -dimethylly-sine and N -trimethyllysine with the N -dimethyllysine predominating. Pea seedling H4 is not methylated and H3 exits as N -mono- and N -dimethyllysine with N -trimethyllysine not being detectable [147,148]. 

The temporal sequence of H3 and H4 methylation after synthesis has been examined in Ehrlich ascites tumor cells [144] and trout testis [149]. Methylation lagged histone synthesis, and the histone was methylated after being bound to DNA. H4 methylation follows the stepwise acetylations and deacetylations [149]. It was suggested that methylation was involved in final arrangement of H3 and H4 on newly replicated DNA [144] and might be involved in histone interactions with other proteins such as histone kinases [149]. 

Histone methylation is a relatively stable modification with a slow turnover rate. However, there is evidence of methyl group turnover for HeLa H3 [150]. It remains to be shown if this histone demethylase activity is present in transformed, but not normal cells. 

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Histone methylation is a common posttranslational modification fond in histones. Histone methylations have been identified on lysine and arginine residues. In case of lysines S-adenosyl-methionine (SAM) dependent methyl transferases catalyze the transfer of one, two or three methyl groups. Lysine methylation is reversible and lysine specific demethylases have been... 

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

Xiao B, Wilson JR, Gamblin SJ (2003) Set domains and histone methylation. Curr Opin Struct Biol 13 699-705... 

Cheng X, Collins RE, Zhang X (2005) Structural and sequence motifs of protein (histone) methylation enzymes. Annu Rev Biophys Biomolec Struct 34 267-294... 

Figure 2 Known inhibitors of histone methylation by KMTs and AMTs.

Rice JC, Allis CD (2001) Histone methylation versus histone acetylation new insights into epigenetic regulation. Cutr Opin Cell Biol 13 263-273... 

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...

Grewal SI, Rice JC (2004) Regulation of heterochromatin by histone methylation and small RNAs. Curr Opin Cell Biol 16 230-238... 

Vassen L, Fiolka K, Moroy T (2006). Gfilb alters histone methylation at target gene promoters and sites of gamma-satellite containing heterochromatin. EMBO J 25 2409-2419 Verdel A, Moazed D (2005) RNAi-directed assembly of heterochromatin in fission yeast. EEBS Lett 579(26) 5872-5878... 

Histone methylation is another posttranslational modification which involves a transfer of a methyl group from the methyl donor S-adenosyl methionine (SAM) to lysine or arginine residues (Fig. 1). In sharp contrast with histone acetylation, this modification occurs particularly in histones H3 and H4 with a remarkable specificity (Kouzarides, 2002 Shilatifard, 2006) (Fig. 1, Table 2). Another feature of histone methylation is that a large fraction of histones in mature chromatin is... 

Zeng L, Zhou MM (2002) Bromodomain an acetyl-lysine binding domain. EEBS letters 513 124-128 Zhang Y, Reinberg D (2001) Transcription regulation by histone methylation interplay between different covalent modifications of the core histone tails. Genes Dev 15 2343-2360... 

Apart from this HDACs are also associated with a number of other epigenetic repression mechanisms including histone methylation, polycomb group of proteins and DNA methylation (discussed later). The class II HDACs have been found to be involved in muscle development, particularly HDAC 5 and 9 knockouts or mutants show evidence of cardiac hypertrophy in a age or stress dependent manner (Zhang et al, 2002 Chang et al, 2004). 

Figure 3. Schematic representation of the interplay of the various epigenetic marks and its therapeutic potential DNA methylation causes the concomitant deacetylation of the histones, whereby it negatively (—) coixelates with histone acetylation and positively (+) with histone methylation, particularly the repressive marks. The active methylation marks correlate positively with histone acetylation. The loss of activity or the loss or mistargeting of these activities are the most common cause of epigenetic diseases. Shown in the boxes are the small molecular modulators (a, activators or i, inhibitors) of the various enzymes that have potential to develop epigenetic therapeutics...

Moscinski L, Atadja P, Bhalla K (2004) Superior activity of the combination of histone deacetylase inhibitor LAQ824 and the FLT-3 kinase inhibitor PKC412 against human acute myelogenous leukemia cells with mutant FLT-3. Clin Cancer Res 10 4991 997 Bali P, Pranpat M, Bradner J, Balasis M, Fiskus W, Guo F, Rocha K, Kumarawsamy S, Boyapalle S, Atadja P, Seto E, Bhalla K (2005) Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90 a novel basis for antileukemia activity of histone deacetylase inhibitors. J Biol Chem 280(29) 26729-26734 Bannister AJ, Schneider R, Kouzarides T (2002) Histone methylation Dynamic or static Cell 109 801-806... 

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