Knockdown of the transcription regulators Spt5 and dom in Drosophila photoreceptors results in premature retinal degeneration and transcriptional signature similar to old flies
Aging is associated with a decline in visual function and increased prevalence of ocular disease, correlating with changes in the transcriptome and epigenome of cells in the eye. Here, we sought to test if age-associated changes in gene expression patterns in the eye directly contribute to the increased risk of retinal degeneration. To do this, we performed a targeted photoreceptor specific RNAi screen in Drosophila to identify gene regulatory factors that result in premature, age-dependent retinal degeneration. From an initial set of 155 RNAi lines each targeting a unique gene and spanning a diverse set of gene regulatory factors, we identified 18 high confidence target genes whose decreased expression in adult photoreceptors leads to premature and progressive retinal degeneration. The 18 target genes were enriched for factors involved in the regulation of transcription initiation, pausing, and elongation, suggesting that these processes are essential for maintaining the health of aging photoreceptors. To identify the genes regulated by these factors, we profiled the photoreceptor transcriptome in a subset of lines. Strikingly, two of the 18 target genes, Spt5 and domino, show substantially similar changes in gene expression to those observed with advanced age. Together, our data suggests that dysregulation of the mechanisms involved in transcription initiation and elongation plays a key role in shaping the transcriptome of aging photoreceptors. Further, our findings indicate that the age-dependent changes in gene expression not only correlate, but might also contribute to increased risk of retinal degeneration. Overall design: RNA-seq