# Chromatin connects metabolism to circadian gene regulation in the aging eye

> **NIH NIH R01** · PURDUE UNIVERSITY · 2024 · $373,765

## Abstract

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.

## Key facts

- **NIH application ID:** 10770459
- **Project number:** 5R01EY033734-02
- **Recipient organization:** PURDUE UNIVERSITY
- **Principal Investigator:** Vikki Marie Weake
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $373,765
- **Award type:** 5
- **Project period:** 2023-02-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10770459

## Citation

> US National Institutes of Health, RePORTER application 10770459, Chromatin connects metabolism to circadian gene regulation in the aging eye (5R01EY033734-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10770459. Licensed CC0.

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