The Clock:Cycle complex is a major transcriptional regulator of Drosophila photoreceptors that protects the eye from retinal degeneration and oxidative stress

Author summaryAge-associated changes to the retinal transcriptome often correlate with physiological changes often see during aging, such as loss of visual function and increase in cell death. However, the mechanisms that contribute to these transcriptomic changes are poorly understood. Here, we used a genomics/bioinformatics approach to identify transcription factor binding sites with differential activity in aging Drosophila retina outer photoreceptors. Amongst these age-regulated transcription factors, we identify the circadian regulators Clock and Cycle. Using a genetics approach, we find that a photoreceptor-specific disruption of the Clock:Cycle complex makes the Drosophila eye susceptible to light-dependent retinal degeneration, and light-independent increase of oxidative stress, showing that a functional circadian clock contributes to visual health and function in Drosophila. Because disruption of circadian rhythms has been associated with the onset of several age-related eye diseases, our data shows that the Drosophila retina serves as a useful model to study how disruption of the circadian clock contributes to neurodegeneration in the retina. 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 (Clk(DN)) 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 Clk(DN) 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 Clk(DN) 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.