Broad Epigenetic Shifts in the Aging Drosophila Retina Contribute to Its Altered Diurnal Rhythmic Transcriptome

TL;DR

Aging in fruit flies causes widespread changes in retinal gene activity rhythms, linked to epigenetic shifts like altered chromatin and H3K4 methylation.

Contribution

Identifies broad epigenetic changes in aging Drosophila retinas that correlate with altered rhythmic gene expression.

Findings

About 40% of genes in aging Drosophila photoreceptors show altered rhythmic expression.

Aging decreases genome-wide H3K4 methylation levels, correlating with gene expression phase shifts.

Reducing H3K4 methylation in young photoreceptors mimics aging-related rhythmic gene expression changes.

Abstract

Alterations in biological rhythms are a common feature of aging, and disruption of circadian rhythms can exacerbate age‐associated pathologies. The retina is critical for detecting light for both vision and for transmitting time‐of‐day information to the brain, synchronizing rhythms throughout the body. Disruption of circadian rhythms by manipulating the molecular clock leads to premature retinal degeneration in flies and mice, and gene expression rhythms are altered in models of age‐associated ocular disease. Despite this, it is unknown how or why the gene expression rhythms of the retina change with age. Here, we show that ~70% of the Drosophila transcriptome is rhythmically expressed throughout the diurnal cycle, with ~40% of genes showing altered rhythms with age. These transcriptome‐wide changes in aging photoreceptors are accompanied by shifts in the rhythmic patterns of RNA Polymerase II (Pol II) occupancy, histone H3 lysine 4 (H3K4) methylation, and chromatin accessibility, without major changes in the occupancy of the circadian clock transcription factors Clock (Clk) and Cycle (Cyc). Instead, aging decreases genome‐wide levels of several different histone methyl marks including H3K4 methylation, whose relative levels across the day correlate with the phase of rhythmic gene expression. Moreover, reduction of H3K4me3 by the knockdown of the three methyltransferases in young photoreceptors results in massive changes to rhythmic gene expression under diurnal light conditions. We conclude that there are broad epigenetic shifts in the aging retina that correlate with and may contribute to widespread alterations in rhythmic gene expression.

As flies age, their photoreceptor transcriptome is extensively reprogrammed, with about 40% of genes undergoing rhythmic expression changes. These transcriptional changes are accompanied by altered RNA Polymerase II occupancy, chromatin accessibility, and H3K4 methylation, without major changes to the occupancy of the core clock transcription factors, Clock and Cycle. Decreasing H3K4 methylation by knocking down each of the three H3K4 methyltransferases in the retina leads to massive rhythmic gene expression changes that parallel the ones that occur during aging.

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