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Chromatin connects metabolism to circadian gene regulation in the aging eye

Award Number: R01EY033734
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Chromatin connects metabolism to circadian gene regulation in the aging eye - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $373,390 )
2025	2025	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Vision Research	000	3	11/27/2024	NON-COMPETING CONTINUATION	$373,390
														Subtotal = $373,390

Issue Date FY: 2024 ( Subtotal = $373,765 )
2024	2024	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Vision Research	000	2	1/11/2024	NON-COMPETING CONTINUATION	$373,765
														Subtotal = $373,765

Issue Date FY: 2023 ( Subtotal = $373,827 )
2023	2023	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Vision Research	000	1	1/27/2023	NEW	$373,827
														Subtotal = $373,827

Grand Total All Awards = $1,120,982

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Chromatin connects metabolism to circadian gene regulation in the aging eye

Award Number: R01EY033734

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/01/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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