An ambitious EC-funded research initiative on epigenetics advancing towards systems biology

While different models are discussed, the question is best provisionally explained by a classical, simplified example(1,2): The phosphate groups connecting the nucleotides of a DNA chain are negatively charged. In naked dsDNA they would repel each other, and the DNA would represent an 'open chromatin' conformation. However, the extruding N termini of nucleosomes are positively charged. Thus, in chromatin consisting only of DNA and nucleosomes the positive histone N-termini would interact with the negative phosphate groups such that the chromatin is highly compacted ('closed chromatin'). There are high levels of H1 linker histones in this chromatin. In a closed chromatin environment genes cannot be transcribed as the transcription factors are sterically hindered to trigger mRNA synthesis - the genes are 'silenced'. The condensed chromatin however can be relaxed by covalently linking acetylgroups (CH3COO-) especially to the amino groups of Lys of the core histones H3 and H4. Acetylation brings in a negative charge and neutralizes the interaction of the N termini with the phosphate groups. As a consequence, the condensed chromatin is transformed into a transiently relaxed structure (see Fig.1) which allows genes to be transcribed. The enzyme catalyzing acetylation is called histone acetyltransferase. Naively one might assume that starting from a zygote, an organism should successively activate all available genes during development in order to live. Thus, at adult age, all genes should be active. However, the simultaneous activity of all genes would produce an uncontrolable chaos of gene expression patterns not allowing coordinated cell- and organ-differentiation. Therefore, many genes need to be more or less permanently inactivated after they have done their job. Such a status can be triggered and maintained by an epigenetic tag. In our example the tag is the methylation of cytosine. Genes which are methylated by a DNA methyltransferase are recognized by the protein MeCP2 which binds to the methylated nucleotides. This protein is complexed with histone deacetylase. Once MeCP2 binds to methylated DNA, histone deacetylase removes the acetyl groups, and the chromatin becomes condensed and inaccessable again for transcription factors. The silenced chromatin can be maintained over most of an organisms lifespan. An example for a protein mediating such a task is encoded by the polycomb gene.

1. Jones, P. L., G. J. Veenstra, P. A. Wade, D. Vermaak, S. U. Kass, N. Landsberger, J. Strouboulis, and A. P. Wolffe. 1998. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet 19:187-91.

2. Nan, X., H. H. Ng, C. A. Johnson, C. D. Laherty, B. M. Turner, R. N. Eisenman, and A. Bird. 1998. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393:386-9.

Figure.1. Bestor, T. H. 1998. Gene silencing. Methylation meets acetylation. Nature 393:311-2. The effects of cytosine methylation and histone deacetylation on transcription. Transcriptional silencing in vertebrates is usually associated with the presence of 5-methylcytosine (m5C) in the DNA. Nan et al.1 and Jones et al.2 have now discovered a link between methylation and histone deacetylation — MeCP2 (a protein that binds methylated DNA) exists in a complex with histone deacetylase