Epigenetic regulation of an IAP retrotransposon in the aging mouse: progressive demethylation and de-silencing of the element by its repetitive induction.
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.
Barbot
Willy
W
Unité des Rétrovirus Endogènes et Eléments Rétroïdes des Eucaryotes Supérieurs, UMR 1573 CNRS, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France.
Dupressoir
Anne
A
Lazar
Vladimir
V
Heidmann
Thierry
T
D000375:Aging / Q000235:genetics*; D000818:Animals; D002478:Cells, Cultured; D002940:Circadian Rhythm / Q000235:genetics*; D019175:DNA Methylation; D020868:Gene Silencing; D007426:Genes, Intracisternal A-Particle / Q000235:genetics*; D022781:Hepatocytes; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008957:Models, Genetic; D009687:Nuclear Proteins; D009928:Organ Specificity; D011401:Promoter Regions, Genetic / Q000235:genetics; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018626:Retroelements / Q000235:genetics*; D013269:Stochastic Processes; D013997:Time Factors; D014157:Transcription Factors
D009687:Nuclear Proteins; D011506:Proteins; D012333:RNA, Messenger; D018626:Retroelements; D014157:Transcription Factors; C102804:nocturnin