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

Abstract

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.