The Epigenetics of RPE Aging

Progress Updates

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.