Mechanisms for methylation-mediated gene silencing and aging.

Gene silencing is often mediated by CpG methylation of key protein binding sites within gene regulatory sequences (GRSs). An aging mechanism is proposed based on this gene-silencing phenomenon whereby accumulation over time of methylation within GRSs contributes to cellular senescence. The proposed molecular mechanism for age-related gene silencing is the spreading of methylation through the regulatory sequences of genes resulting in progressive reduction of gene transcription. There is considerable experimental evidence for methylation spreading and its role in gene silencing, but the mechanism responsible for this process has not been elucidated. A four-step mechanism is proposed whereby an original methylation occurs, methyltransferase (MTase) molecules progressively move 5' to 3' from this site, neighboring CpG dinucleotides become methylated, and diminished gene expression ensues. Over time, this process may lead to widespread gene silencing in diverse dividing and nondividing cell types contributing to aging of the organism.