An important question in determining the intersection of aging and biological mechanisms of eye diseases is whether age-related changes in epigenetic processes drive the transition from aging to early disease state in ocular diseases of aging such as age-related macular degeneration. During aging and the pathogenesis of ocular disease, significant changes in chromatin correlate with, and contribute to, misregulation of gene expression. It is therefore important to understand how epigenetic processes contribute to age-dependent changes in gene expression and visual function in the eye, so that effective therapeutic interventions for late- onset retinal degenerative diseases can be developed. The long-term goal is to elucidate the underlying epigenetic processes that contribute to aging in the eye, and that can be targeted to restore youthful transcriptional programs and thus prevent the transition from aging to ocular disease. The objective of this application is to identify the epigenetic mechanisms that contribute to aging in photoreceptors using Drosophila - an excellent model for both epigenetics and aging due to its short life-span and amenability to genetic manipulation. The central hypothesis is that stochastic defects in epigenetic processes that activate transcription contribute to age-related decreases in photoreceptor gene expression and loss of visual function. This hypothesis is highly relevant to age-related ocular diseases in humans because it supports a model in which modest defects in transcriptional activation lead to a reduction in the levels of key proteins in individual photoreceptor cells within the eye, leading to progressive defects in visual function and eventual photoreceptor degeneration. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Characterize the contribution of epigenetic activation to age-dependent transcriptional changes in photoreceptors; and 2) Identify the epigenetic factors that maintain active transcription in aging photoreceptors. Under the first aim, genome-wide and single-cell approaches will be used to determine the overlap between changes in gene expression and chromatin modifications that result from aging, and changes that result from misregulation of specific epigenetic processes that activate transcription such as histone acetylation and histone deubiquitylation. Under the second aim, an age-dependent defect in the ability of photoreceptors to recover rhodopsin levels and localization following blue-light stress will be used as a sensitized system in which to identify epigenetic factors that are required to maintain active transcription in aging photoreceptors. The rationale for the proposed research is that its successful completion is expected to identify novel epigenetic targets for therapies to delay or prevent late-onset retinal degeneration. This research is significant because an understanding of these fundamental epigenetic mechanisms is critical to develop therapeutic interventions against ocular diseases associated with aging, in which epigenetic processes might contribute to disease onset, severity or progression.
Epigenetic mechanisms play an important role in regulating gene expression, and have been implicated in aging and in the pathogenesis of ocular disease. The studies proposed in this application are directly relevant to the NEI Audacious Goal of determining the intersection of aging and biological mechanisms of eye disease by identifying epigenetic mechanisms that might cause or allow the transition from aging to early disease state in ocular diseases of aging.
