Age-dependent Modifications of Retinal Pigmented Epithelium Genomic DNA
The Epigenetics of RPE Aging
Current evidence supports the hypothesis that inherent age-dependent losses in the retinal pigmented epithelium's capacity to maintain, repair, and regenerate contributes to the onset and progression of AMD. Cell type is determined, in large part, by modification of DNA and chromatin. This proposal seeks to determine whether age-dependent changes in DNA methylation can explain the age-related decline in retinal pigmented epithelium function.
Changes in retinal pigment epithelium (RPE) cells due to age and environmental stress may be associated with the onset and progression of age‐related macular degeneration (AMD). These pressures can cause changes in gene activity and cell health through a process called epigenetics. This process, where genes are either activated or inactivated by the addition of specialized chemical groups to the DNA, occurs naturally during development and plays a key role in the determination of cellular function. Dr. Monte Radeke and collaborators will determine if changes to the original epigenetic programming of RPE can help explain the damage observed in AMD. They will use a state‐of‐the-art global analytical method to identify genes in both cultured RPE cells and human donor RPE whose epigenetic programming becomes altered with increasing age. If aging does cause epigenetic changes to genes in RPE cells, this research could lead to new treatments for AMD.
Current evidence suggests that inherent age-dependent losses in retinal pigmented epithelium (RPE) function contribute to the onset and progression of AMD. A person’s genome contains all of the information required to generate the various cell types in a body. During the course of development each unique cell type is determined, in large part, through a process known as “epigenetic modification” (changes that happen without changing the spelling of the DNA). The most fundamental epigenetic modification results from site-specific DNA “methylation” (the adding of a chemical “methyl” group to DNA that often results in altered gene expression). The resulting pattern of methylation is referred to as the methylome. Although once considered permanent, recent studies have shown that changes in the methylome are associated with aging and cancer. Aging is the one universal risk factor for AMD.. Dr. Radeke’s team has directed their research efforts at determining if age-associated changes in the RPE methylome could contribute to the onset and/or progression of AMD.
In year one of this project, the team has used a RPE cell culture model of AMD to determine if 'age'-dependent changes in the RPE methylome are associated with loss of capacity to differentiate. By measuring the expression of all known genes, the team has determined that there are widespread age-related changes in the relative expression of genes involved in cell division. Interestingly, the 'aged' RPE maintain relatively normal levels of RPE-specific gene expression while they are actively growing. It is only after they stop growing that wholesale differences in RPE-specific gene expression become pronounced, suggesting that only a few regulators of gene expression may be responsible for this transformation. To determine if changes in the RPE specific methylome might underlie this phenomenon, the team has used a state-of-the-art, next-generation DNA sequencing method to survey the entire RPE methylome. This analysis has identified thousands of differences in DNA methylation between 'young' and 'old' cultured RPE. Roughly 80% of the differences result from new methylation, the remaining differences result from loss of methylation. While many of these changes may be inconsequential with respect to gene expression, there is an overall enrichment for several key genes believed to regulate RPE differentiation. In the coming year, Dr. Radeke’s team will extend these analyses to native RPE obtained from young and old donor eyes to determine if a similar process is occurring in the eye. If this proves true, this would suggest that DNA methylation is a new target for the development of AMD therapeutics.
About the Researcher
Dr. Monte Joel Radeke is a Project Scientist in the Center for the Study of Macular Degeneration at the University of California, Santa Barbara and is the Technical Director for the Neuroscience Research Institute's Genomics and Proteomics Shared Resource Facility. He received his doctoral degree in Neurosciences at Stanford University. His research centers on the application of state-of-the-art "omics" technologies to further our understanding of the molecular basis underlying age-related macular degeneration. He focuses on the processes of aging, drusen biogenesis, and inflammation. In addition to these basic science studies, Radeke is working with the California Project to Cure Blindness, a multicenter disease team whose efforts are directed at the development of a stem-cell-based therapy for the treatment of AMD.
First published on: Wednesday, July 6, 2011
Last modified on: Friday, March 22, 2013