Department of Biochemistry, Purdue University, West Lafayette, Indiana, United States of America.
Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, Indiana, United States of America.
PLoS Genet. 2022 Jan 31;18(1):e1010021. doi: 10.1371/journal.pgen.1010021. eCollection 2022 Jan.
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.
衰老的眼睛会经历生理变化，包括视觉功能下降和视网膜变性风险增加。尽管衰老的视网膜中有与这些生理变化相关的转录组特征，但导致衰老过程中细胞内稳态的基因调控机制仍有待确定。在这里，我们整合了 ATAC-seq 和 RNA-seq 数据，鉴定出 57 种在衰老果蝇光感受器中表现出差异活性的转录因子。这 57 种年龄调节转录因子包括两种昼夜节律调节剂 Clock 和 Cycle，它们在衰老过程中表现出持续增加的活性。当我们通过在成年光感受器中表达显性失活版本的 Clock (ClkDN) 来破坏 Clock:Cycle 复合物时，我们观察到 15-20%的基因表达发生变化，包括光转导机制的关键组成部分和许多眼睛特异性转录因子。通过 ATAC-seq，我们表明 ClkDN 在光感受器中的表达导致 37 种转录因子活性的变化，并导致光感受器中全局染色质可及性水平的逐渐下降。支持时钟依赖性转录在眼睛中的关键作用，ClkDN 在光感受器中的表达也诱导光依赖性视网膜变性和氧化应激增加，而与光暴露无关。总之，我们的数据表明，昼夜节律调节剂 Clock 和 Cycle 通过指导维持光转导机制表达和对抗氧化应激的基因调控网络，作为衰老眼睛中的神经保护因子发挥作用。
