Epigenetic regulation of an IAP retrotransposon in the aging mouse: progressive demethylation and de-silencing of the element by its repetitive induction

摘要

The recent insertion of a murine intracisternal A-particle (IAP) retrotransposon within one of the introns of a housekeeping gene, the circadian m.nocturnin gene, revealed a singular expression profile, both throughout the daytime and the mouse life span. Measurement of the levels of transcripts from this element by quantitative real-time RT–PCR, in organs of 1–24-month-old mice, disclosed that the inserted element—which is part of a large family of otherwise severely repressed mobile elements—becomes active upon aging, specifically in the liver where the m.nocturnin housekeeping gene is expressed in a circadian manner and induces a circadian expression of the IAP sequence. This age-dependent induction is cell-autonomous, as it persists in hepatocytes in primary culture. We further show, using methylation-sensitive enzymes, a correlation between the life-time kinetics of this process and a liver-specific demethylation of the IAP promoter. These results strongly support a model whereby the progressive demethylation and turning on of the IAP sequence is the sole result of the transient, daily activation—throughout the mouse life span—of its promoter. This phenomenon, which develops on a timescale of months to years in the aging mouse, might reveal a general epigenetic—and stochastic—process, which could account for a large series of events associated with cell and animal aging.