Research Article: Transposable elements become active and mobile in the genomes of aging mammalian somatic tissues

Date Published: December 7, 2013

Publisher: Impact Journals LLC

Author(s): Marco De Cecco, Steven W. Criscione, Abigail L. Peterson, Nicola Neretti, John M. Sedivy, Jill A. Kreiling.



Transposable elements (TEs) were discovered by Barbara McClintock in maize and have since been found to be ubiquitous in all living organisms. Transposition is mutagenic and organisms have evolved mechanisms to repress the activity of their endogenous TEs. Transposition in somatic cells is very low, but recent evidence suggests that it may be derepressed in some cases, such as cancer development. We have found that during normal aging several families of retrotransposable elements (RTEs) start being transcribed in mouse tissues. In advanced age the expression culminates in active transposition. These processes are counteracted by calorie restriction (CR), an intervention that slows down aging. Retrotransposition is also activated in age-associated, naturally occurring cancers in the mouse. We suggest that somatic retrotransposition is a hitherto unappreciated aging process. Mobilization of RTEs is likely to be an important contributor to the progressive dysfunction of aging cells.

Partial Text

Aging is the primary risk factor for multiple diseases that are responsible for considerable morbidity and mortality, including dementias, cardiovascular diseases, diabetes and cancer. While aging is clearly multi-factorial, an important driver is believed to be the accumulation of DNA damage and epigenetic changes that lead to genome instability over time, especially in disorders such as cancer [1]. Genome integrity is maintained by multiple pathways involving the DNA damage response machinery and chromatin remodeling complexes. These pathways, which are normally highly efficient, begin to lose their effectiveness with age contributing to destabilization of the genome [2-4]. Multiple environmental as well as endogenous sources of DNA damage have been documented. One potentially important mechanism impacting genome stability is the activation of endogenous transposable elements (TEs), which can result in insertional mutagenesis, DNA damage and genome rearrangements [5].

The inability to maintain complex biological structures contributes to the onset of tissue dysfunction and the eventual demise of organisms as they age. During replicative senescence of human fibroblasts chromatin is subject to extensive changes in the global distribution of euchromatin and heterochromatin [25,35]. We found that the fundamental architecture of the genome undergoes profound alterations: an overall closing of chromatin in euchromatic gene-rich regions, which is opposed by a somewhat paradoxical relaxation of heterochromatin in gene poor and pericentromeric regions [25]. The gene-poor regions overlap significantly with lamin-associated domains (LADs), are marked by H3K9Me3, and replicate late during S phase [35]. The relative closing of euchromatic regions was associated with a dampening of global gene expression, and the relaxation of heterochromatic regions with increased transcription of RTEs, many of which are localized in LADs and are normally heavily heterochromatinized to prevent their expression.





Leave a Reply

Your email address will not be published.