Our Science – Oberdoerffer Website
Philipp Oberdoerffer, Ph.D.
Genomic instability and changes in gene expression are conserved hallmarks of eukaryotic aging. The accumulation of mutations and chromosomal aberrations, as well as the progressive loss of 'youthful' gene expression patterns, have been associated with altered cell function and a greater propensity for age-related diseases, including a variety of neurodegenerative disorders and malignant transformation. Work from the budding yeast S. cerevisiae implies DNA damage as a major contributor to the large scale genomic changes that characterize yeast aging, and accumulating evidence suggests that similar processes may be at work during mammalian aging. Elucidating the impact of the DNA damage response on chromatin organization is, thus, vital to improve our understanding of often detrimental, age-related (epi-)genomic changes and the associated organismal decline, and may eventually help to promote genomic stability and maintain a more youthful epigenetic profile.
We found previously that the SIRT1 deacetylase provides a critical link between DNA repair, aging and malignant transformation, and that augmenting SIRT1 activity is sufficient to delay tumorigenesis and suppress age-related gene expression changes in mice. SIRT1 is thought to be responsible for the health-benefits of a dietary regimen called calorie restricition (CR) and these findings may in part explain the reversal of genomic changes and tumor development observed in repsonse to CR.
Our work further led to the more general hypothesis that a DNA damage-induced redistribution of chromatin modifiers (or 'RCM response') may underlie the alterations in gene expression and genomic stability that characterize eukaryotic aging. While this idea was primarily inspired by yeast findings, our studies on the mammalian chromatin modifier SIRT1 provides evidence that the RCM response is a conserved cause of aging, and that SIRT1 and its orthologs are critically involved.
In a continuing effort to understand how DNA damage and its repair affect the (epi-)genome over a lifetime, and how these changes impinge on tissue homeostasis, cancer and aging, we investigate (i) the role of SIRT1 and other chromatin modifiers during DNA repair and mutagenesis in vitro and in vivo, and (ii) the molecular basis and physiological relevance of DNA damage-induced epigenetic changes with regard to age-related diseases, (stem) cell homeostasis and malignant transformation.
We have developed a range of tissue-specific SIRT1-deficient or -overexpressing mouse strains to determine how SIRT1 affects genetic and epigenetic integrity in vivo. We are further generating a mouse model for the conditional induction of DNA strand breaks, which, by itself and in combination with SIRT1 mutant mice, will provide a unique tool to study the role of a defined DNA repair process and the associated epigenomic changes in mammalian aging and disease progression. We use a combination of genome-wide mapping of epigenetic changes and the associated transcriptional deregulation, molecular biology and animal studies to dissect the molecular pathways of aging and to expand our knowledge of the regulation of DNA repair by changes in chromatin structure beyond the role of SIRT1.
The potential of DNA damage to affect cell function both through direct DNA alterations and through indirect, epigenetic changes in chromatin structure puts it at a critical position to influence the aging of eukaryotes. The long term goal of my group is to understand how DNA damage and its repair affect the (epi-)genome over a lifetime, and how these changes impinge on tissue homeostasis, cancer and aging.
This page was last updated on 3/8/2013.