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

Nucleic Acids Res. 2002 Jun 1;30(11):2365-73. doi: 10.1093/nar/30.11.2365.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics*
  • Animals
  • Cells, Cultured
  • Circadian Rhythm / genetics*
  • DNA Methylation*
  • Gene Silencing*
  • Genes, Intracisternal A-Particle / genetics*
  • Hepatocytes
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Models, Genetic
  • Nuclear Proteins
  • Organ Specificity
  • Promoter Regions, Genetic / genetics
  • Proteins / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Retroelements / genetics*
  • Stochastic Processes
  • Time Factors
  • Transcription Factors

Substances

  • Nuclear Proteins
  • Proteins
  • RNA, Messenger
  • Retroelements
  • Transcription Factors
  • nocturnin