Abstract
The aging eye experiences physiological changes that include decreased visual function and increased risk of retinal degeneration. Although there are transcriptomic signatures in the aging retina that correlate with these physiological changes, the gene regulatory mechanisms that contribute to cellular homeostasis during aging remain to be determined. Here, we integrated ATAC-seq and RNA-seq data to identify 57 transcription factors that showed differential activity in aging Drosophila photoreceptors. These 57 age-regulated transcription factors include two circadian regulators, Clock and Cycle, that showed sustained increased activity during aging. When we disrupted the Clock:Cycle complex by expressing a dominant negative version of Clock (ClkDN) in adult photoreceptors, we observed changes in expression of 15-20% of genes including key components of the phototransduction machinery and many eye-specific transcription factors. Using ATAC-seq, we showed that expression of ClkDN in photoreceptors leads to changes in activity of 37 transcription factors and causes a progressive decrease in global levels of chromatin accessibility in photoreceptors. Supporting a key role for Clock-dependent transcription in the eye, expression of ClkDN in photoreceptors also induced light-dependent retinal degeneration and increased oxidative stress, independent of light exposure. Together, our data suggests that the circadian regulators Clock and Cycle act as neuroprotective factors in the aging eye by directing gene regulatory networks that maintain expression of the phototransduction machinery and counteract oxidative stress.
Highlights
One of the hallmarks of the aging eye, as well as many age-related eye diseases, is the loss of photoreceptor function and survival [1,2]
We find that a photoreceptor-specific disruption of the Clock:Cycle complex makes the Drosophila eye susceptible to lightdependent retinal degeneration, and light-independent increase of oxidative stress, showing that a functional circadian clock contributes to visual health and function in Drosophila
Using a dominant negative mutant of Clock (ClkDN) that disrupts the Clk:Cyc complex and abolishes rhythmic transcription, we showed that the Clk:Cyc complex has an integral role in controlling gene expression of 15–20% of active genes, and maintaining global levels of chromatin accessibility in photoreceptors
Summary
One of the hallmarks of the aging eye, as well as many age-related eye diseases, is the loss of photoreceptor function and survival [1,2]. Disruption of epigenetic mechanisms is associated with the onset of age-related eye diseases, such as age-related macular degeneration [6,7], suggesting that transcriptional regulation contributes to the changes in homeostasis that are observed in the aging eye. We still have only a basic understanding of how the molecular mechanisms that drive the age-associated changes in the transcriptome increase the risk of ocular disease with advanced age. Transcription factors (TF) function as regulatory hubs of gene expression programs in a highly-tissue specific manner. ATAC-seq analysis of retinal pigmented epithelium from patients with age-related macular degeneration identified global changes in chromatin accessibility at the onset of the disease state, suggesting that differential activity of regulatory elements strongly contributes to the initial stages of age-associated ocular disease [16]. Identification of TFs with differential activity in the aging eye could provide insight into the mechanisms that contribute to the increased risk of retinal degeneration during aging
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