Regulation Of Gene Expression Chromatin and DNA Methylation

Biophysics and molecular biology have revealed that chromatin consists of a repetitive nucleoprotein complex, the nucleosome. This particle consists of a histone octamer, with two copies of each of the histones (H2A, H2B, H3, and H4), wrapped by 147 base pairs of DNA. In the octamer, histones H3 and H4 are assembled in a tetramer, which is flanked by two H2A-H2B dimers. A variable length of DNA completes the second turn around the histone octamer and interacts with a fifth histone, H1. H2A, H2B, H3, and H4 are variously modified at their amino- and carboxyl-terminal tails to influence the dynamics of chromatin structure and function (Ballestar and Esteller 2002; Keshet et al. 1986; Kornberg and Lorch 1999; Strahl and Allis 2000). Although chromatin provides structure to chromosomes, it also plays a critical role in transcriptional regulation in eukaryotes because it can repress gene expression by inhibiting the ability of transcription factors to access DNA. In fact, chromatin ensures that genes are inactive until their expression is commanded. In the activation process, cells must attenuate nucleosome-mediated repression of an appropriate subset of genes by means of activator proteins that modify chromatin structure. An activator protein displaces nucleosomes, which permits a complex of proteins (general transcription factors) to bind DNA at a promoter and to recruit RNA polymerase.

Cytosine methylation at CpG dinucleotides is the most common modification of the eukaryotic genome. In vertebrates, methylation occurs globally throughout the genome, with the exception of CpG islands. These are CG-rich regions of DNA that stretch for an average of ~1 kilobase (kb), coincident with the promoters of 60% of human RNA polymerase II-transcribed genes. Methylation of cytosines at CpG represses transcription (Ballestar and Esteller 2002). Genetic imprinting, a process by which particular paternal or maternal genes are inactivated throughout a species, is at least partly controlled by DNA methylation. Specific proteins binding to methylated DNA may establish a bridge between chromatin and DNA methylation. They recruit histone deacetylases (HDACs) to activate a methylated promoter, which in turn deacetylates histones, leading to a repressed state (Ballestar and Esteller 2002; Keshet et al. 1986).

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