MECHANISMS FOR METHYLATION-MEDIATED GENE SILENCING AND AGING

Gene silencing is often mediated by CpG methylation of key protein bin ding sites within gene regulatory sequences (GRSs). An aging mechanism is proposed based on this gene-silencing phenomenon whereby accumulat ion over time of methylation within GRSs contributes to cellular senes cence. The proposed molecular mechanism for age-related gene silencing is the spreading of methylation through the regulatory sequences of g enes resulting in progressive reduction of gene transcription. There i s considerable experimental evidence for methylation spreading and its role in gene silencing, but the mechanism responsible for this proces s has not been elucidated. A four-step mechanism is proposed whereby a n original methylation occurs, methyltransferase (MTase) molecules pro gressively 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.