Methylation and the genome: the power of a small amendment

Abstract

Methylation is a major regulator of mammalian genome function in vivo. The methylation of DNA on cytosine residues is a critical component of the host genome defense pathway against the expansion of repetitive DNA and is central to such epigenetic phenomena as monoallelic expression of genes regulated by imprinting and dosage compensation. Deregulation of the DNA methylation pathway leads to aberrant gene repression in cancer and contributes to cell cycle misregulation. Transcriptional repression of methylated DNA loci results from a poorly understood interplay between various chromatin-based regulatory machines, such as histone deacetylases, and auxiliary pathways. Intranuclear protein methylation also has considerable regulatory impact: this includes the function of histone methyltransferases in establishing regions of transcriptionally inert heterochromatin and of protein methyltransferases in mediating transcriptional activation by the nuclear hormone receptors. An important thermodynamic distinction between methylation and many other covalent modifications of intracellular components-e.g., phosphorylation or acetylation-is the relative chemical stability of the methylated form of an amino acid (typically, lysine or arginine) compared with its cognate acetylated form. Thus, a protein, once methylated, may persist in that state. Together with the well characterized role of DNA methylation in long-term ("epigenetic") modes of gene expression, this points to methylation in general as a chemical modification that is associated with enabling stable patterns of genome behavior. Considering the ubiquity of methylation in genome control pathways, it is possible that dietary imbalance affecting methyl-generating pathways may contribute to genome misregulation and disease etiology by affecting the ability of the nucleus to maintain methylation of its components at physiological levels.