Age-associated activation of epigenetically repressed genes in the mouse.

Epigenetic control of gene expression is a consistent feature of differentiated mammalian cell types. Epigenetic expression patterns are mitotically heritable and are stably maintained in adult cells. However, unlike somatic DNA mutation, little is known about the occurrence of epigenetic change, or epimutation, during normal adult life. We have monitored the age-associated maintenance of two epigenetic systems--X inactivation and genomic imprinting--using the genes Atp7a and Igf2, respectively. Quantitative measurements of RNA transcripts from the inactive and active alleles were performed in mice from 2 to 24 months of age. For both genes, older animal cohorts showed reproducible increases in transcripts expressed from the silenced alleles. Loss of X chromosome silencing showed cohort mean increases of up to 2.2%, while imprinted-gene activation increased up to 6.7%. The results support the hypothesis that epigenetic loss of gene repression occurs in normal tissues and may be a contributing factor in progressive physiological dysfunction seen during mammalian aging. Quantitatively, the loss of epigenetic control may be one to two orders of magnitude greater than previously determined somatic DNA mutation.