Epigenetics DNA methylation

Although genetic variation in many genes may be associated with differential drug responses, it is also apparent that other factors, such as epigenetics (DNA methylation, interference RNA, RNA editing, histone acetylation/deacetylation. 

In higher eukaiyotes, most of the chromosomal DNA carries 5-methyl-cytidine residues located in CpG sequence motives. There is a close correlation between transcriptional inactivation and methylation. On the other hand, considerable evidence shows that regions of DNA that are actively engaged in transcription lack 5-methyl-cytidine nucleotides in CpG motivs. Hence DNA methylation is a means how cells regulate gene expression. DNA methylation which is catalyzed by DNA methyltransferases is the best characterized epigenetic mechanism. 

Epigenetic is a term used to describe a state of gene expression that is mitotically and meiotically inherited without any change in the sequence of DNA. Epigenetic mechanisms are mainly of two classes (1) the DNA may be modified by the covalent attachment of a moiety that is then perpetuated. (2) a self-perpetuating protein state may be established (Zelent et al, 2004). The two most studied epigenetic phenomena are DNA methylation and histone tail modifications (Mai et ai, 2005). 

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...

Keywords Bipolar disorder COMT DNA methylation DRDl DRD2 epigenetic MAOA RELN QM-MSP schizophrenia. 

The methylation of DNA at CpG islands has also turned out to be an important regulator for cell development, the differentiated proteome and the regulation of cell survival [237,238]. Indeed the implications of this chemical modification have been linked to DNA accessibility, chromatin fluidity and cell transformation [239,240]. DNA methylation is required for genomic stability and believed to act as an inert epigenetic marker in germinal cells and preimplantation embryos [238]. Presumably, DNA methylation is required for the heritable transmission of chromatin structure, which prevents the expression of terminally silenced genes in differentiated tissues, and provides a host-defense mechanism against parasitic transposable elements [241]. 

Bird, A. (2002) DNA methylation patterns and epigenetic memory. Genes Dev. 16, 6-21. 

The notion that DNA methylation is an epigenetic mechanism that acts in conjunction with post-synthetic modifications of histones and other proteins is nowadays widely accepted and is the focus of major research effort worldwide. It must be noted though that this is probably not the only way through which methylation affects chromatin structure, and that DNA methylation may directly modulate some basic structural features of nucleosomes or the chromatin fibers they form. 

The potency of zebularine is about 10-fold lower than for the azacytosines [73]. Zebularine also inhibits cytidine deaminase [75] which is involved in nucleoside catabolism and deactivates also for example azacitidine and its desoxy analog [76]. Thus, it increases the concentrations of nucleoside triphosphates for incorporation into DNA, the efficacy of DNA methylation and ultimately the anticancer activity of for example azacitidine [77, 78[. Zebularine is metabolized by aldehyde oxidase and ithasbeen shovm that its activity can be increases if an inhibitor of that enzyme, for example raloxifene is given in combination [79]. One big question about all epigenetic drugs is the origin of the observed selectivity towards cancer cells. For zebularine, it has been shown that much less activation towards triphosphate metabolites that can be incorporated into DNA occurs in normal muscle tissue as compared to cancer tissue [80]. 

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