View Program - 63rd Annual Drosophila Research Conference

The chromatin landscape defines cellular identity in multicellular organisms with unique patterns of DNA accessibility and histone marks decorating the genome of each cell type. Further, modulation of the chromatin landscape contributes to the regulation of most nuclear processes, including replication, transcription and DNA repair. Thus, profiling the chromatin state of different cell types in an intact organism under disease or distinct physiological conditions can provide insight into how chromatin regulates cell homeostasis in vivo. 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 changes, the gene regulatory mechanisms that contribute to cellular homeostasis during aging remain to be determined. To identify transcriptional regulatory mechanisms that contribute to the homeostasis of the aging eye, we utilized a tissue-specific approach to profile the transcriptomic and accessible chromatin landscape of Drosophila photoreceptor neuron in an aging time course. ATAC-seq and RNA-seq data integration identified 61 transcription factors that showed differential activity in aging Drosophila photoreceptors. These 61 age-regulated transcription factors included two circadian regulators, Clock (CLK) and cycle (CYC), that showed sustained increased activity during aging. When we disrupted Clock activity in adult photoreceptors using a CLK dominant negative mutant, we observed changes in expression of 15 – 20% of genes including key components of the phototransduction machinery and several eye-specific transcription factors. Using ATAC-seq, we showed that loss of Clock activity leads to changes in activity of 31 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, disruption of Clock activity in photoreceptors also induced light-dependent retinal degeneration and increased oxidative stress, independent of light exposure. Since disruption of circadian rhythms has been recently associated with the onset of many age-related eye diseases, our data suggests that during normal aging, the circadian TF complex CLK:CYC protects the aging retina by directing gene regulatory networks that maintain expression of the phototransduction machinery and counteract oxidative stress.

Tissue-specific chromatin profiling reveals a key role for Clock-dependent transcription in regulation of Drosophila photoreceptor homeostasis