DNA methylation and chromatin structure

DNA methylation and chromatin structure beyond the post-synthetic modifications of histones and other proteins... 

Schmitt, M. and Groudine, M. (2004) Intragenic DNA methylation alters chromatin structure and elongation efficiency in mammalian cells. Nature Structural ej Molecular Biol(, 11, 1068-1075. 

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. 

Apart from DNA methylation studies, the second aspect of epigenetic misregulation involves disruption of histone acetylation and chromatin structure. Functional disruption of some HATs genes (such as the CBP and p300) is detected in some cancers, most notably, acute pro-myelocytic leukemia (51). This has lead to the hope that HD AC inhibitors will be useful for the treatment of this disease and a number of inhibitors are currently being assessed in clinical trials (see below). 

Chromatin is composed of nucleosomes, where each comprise 147 base pairs of DNA wrapped around an octamer oftwo copies of each histone H2A, H2B, H3, and H4. Nucleosomes are folded into higher-order structures that are stabilized by linker histones. Chromatin structure can be altered by enzymes that posttranslationally modify histones (e.g., through phosphorylation, acetylation, methylation, or ubiquitination) or by ATP-driven chromatin-remodeling complexes that alter nucleosome position and/or composition. 

Figure 1. Hierarchical model of chromosome structure, (a) In interphase cells, DNA is packed in a nucleus as forming nucleosome and chromatin, (b) DNA forms nucleosome structure together with core histone octamer, which is then folded up into 30nm fiber with a help of linker histone HI. This 30 nm fiber is further folded into 80 nm fiber and 300 nm loop structures in a nucleus. In mitosis, chromosome is highly condensed. Proteins which are involved in each folding step are indicated above and non-protein factors are indicated below, (c) The amino acid sequences of histone tails (H2A, H2B, H3 and H4) are shown to indicate acetylation, methylation and phosphorylation sites. (See Colour Plate 1.)...

As described above, histones are much more than passive structural players within chromatin. Dynamic post-translational modifications of these proteins confer specialized chemical proprieties to chromatin of both informational and structural nature with important functional implications. The highly conserved sites for acetylation, methylation, phosphorylation, ADP-ribosylation, and ubiquitination events on histone tails appear to orchestrate functional activities that range from transcriptional activation and repression to DNA repair and recombination. 

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]. 

Although chemically modifying DNA have distinctive implications for chromatin transitions and fiber structure in the presence of HI [250], in vivo these effects appear to work in concert with chromosomal proteins. 5 -Methylcytosines are specifically bound by members of the MBD (methyl-CpG-binding-domain) family, such as MeCP2 (Methyl-Cytosine binding Protein 2) and MBDl. These proteins have been shown to interact with HDACs and provide a casual link between DNA methylation, histone deacetylation and transcriptional repression [251-253]. 

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