Oxidative stress contributes to the development and progression of age-related ocular diseases such as age- related macular degeneration, cataracts, glaucoma and diabetic retinopathy. The eye is particularly vulnerable to oxidative stress due to its high metabolism, oxygen content and light exposure. Cells respond to reactive oxygen species by inducing expression of genes that counteract these toxic compounds, but aging impairs the ability of cells to activate these cytoprotective gene expression programs. Induction of stress response genes requires epigenetic mechanisms, and our preliminary studies show that these epigenetic mechanisms are essential in photoreceptors to prevent premature retinal degeneration. Notably, many of the epigenetic factors that protect photoreceptors are themselves subject to protein oxidation, and oxidative stress directly inhibits activity of two of these proteins in vitro. Here, we hypothesize that oxidative stress inhibits the epigenetic mechanisms required for stress gene induction in aging photoreceptors, leading to increased risk of retinal degeneration. In this model, increased oxidative stress due to smoking or other environmental factors, could tip the balance towards ocular disease by impairing the epigenetic mechanisms that are necessary for neuroprotective gene expression. To test this model, we will identify the genes induced by oxidative stress in photoreceptors during aging and in response to blue light, which induces oxidative stress, in the genetically tractable model system Drosophila. Next, we will test if prolonged oxidative stress impairs induction of stress response genes by profiling nascent transcription in photoreceptors exposed to blue light. We have identified 22 epigenetic factors that are required for survival of old photoreceptors, and we will test if these factors increase susceptibility to oxidative stress and are necessary for stress gene induction in photoreceptors. Last, we will characterize the redox proteome of eyes exposed to oxidative stress and test if oxidative stress inhibits the activity of histone modifying enzymes in vitro. Together, these studies will identify the epigenetic factors that are susceptible to inactivation by oxidative stress, but that are also necessary for photoreceptors to cope with oxidative stress. In the long-term, these epigenetic mechanisms could be targeted therapeutically by generating oxidative-insensitive proteins that could enhance the resistance of old photoreceptors to oxidative stress.
Oxidative stress increases with age, and plays a major role in the development and progression of age- associated ocular disease. To counteract oxidative stress, cells activate the expression of stress response genes; a process that is highly regulated by epigenetic mechanisms. We propose that during aging, chronic levels of oxidative stress impair expression of stress response genes by directly oxidizing the key epigenetic factors required for their expression, thereby compromising cell survival and increasing the risk of retinal degeneration.
