Wednesday, December 4, 2024
12/4/2024
Changes in metabolism in the aging eye can affect its epigenome because several metabolic intermediates also act as donor molecules for deposition of epigenetic marks such as histone and DNA methylation. During aging, there are changes in the metabolic pathways that produce the donor molecule required for histone and DNA methylation, S-adenosylmethionine (SAM), from the amino acid methionine. Methionine metabolism is strongly linked to aging across multiple species because restricting methionine intake extends lifespan, and is thought to be responsible for the lifespan extension caused by caloric restriction. In the aging Drosophila eye, we observe changes in methionine metabolism including an increase in levels of S-adenosylhomocysteine (SAH), which inhibits the activity of methyltransferases. This age-associated increase in SAH correlates with decreased levels of histone methylation marks across the entire genome in photoreceptors. Moreover, we show that loss of the methyltransferases that deposit one of these marks in photoreceptors leads to premature retinal degeneration. We propose that the decreased histone methylation in aging photoreceptors contributes to the age-related changes that we observe in gene expression. Specifically, we have identified changes in rhythmic expression of more than a third of active genes in aging photoreceptors together with altered transcription factor binding activity of the circadian master regulators Clock and Cycle. The circadian clock is highly conserved from flies to humans, and maintains biological rhythms by controlling gene expression programs through a series of transcription- translation feedback loops. When we disrupt the circadian clock in photoreceptors, we observe substantial retinal degeneration accompanied by global changes in chromatin accessibility and misregulation of more than a quarter of active genes. Loss of circadian regulators in the mouse eye causes age-dependent retinal degeneration, suggesting that the circadian clock has a conserved role in protecting the aging eye. Based on our preliminary data, we hypothesize that increasing oxidative stress in the aging eye inhibits activity of the sole enzyme that breaks down SAH on chromatin at actively expressed genes. We further propose that the local increases in SAH levels at expressed genes inhibit the activity of histone methyltransferases, leading to changes in the rhythmic expression of genes in the aging eye. Together, these studies provide a framework in which to understand how the normal changes that occur in the aging eye can disrupt its metabolism, leading to changes in the epigenome that disrupt normal patterns of gene expression and increase the risk of ocular disease. Drosophila provides an ideal model for these studies because it shares a similar circadian clock and epigenetic mechanisms with humans, but ages much more rapidly allowing us to examine mechanisms in the context of normal aging in specific cell types in the eye.
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