Department of Eye and Vision Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK.
Department of Ophthalmology, Wolverhampton Eye Infirmary, New Cross Hospital, Wolverhampton, UK.
J Cell Mol Med. 2021 Jun;25(12):5572-5585. doi: 10.1111/jcmm.16569. Epub 2021 May 1.
Ageing presents adverse effects on the retina and is the primary risk factor for age-related macular degeneration (AMD). We report the first RNA-seq analysis of age-related transcriptional changes in the human retinal pigment epithelium (RPE), the primary site of AMD pathogenesis. Whole transcriptome sequencing of RPE from human donors ranging in age from 31 to 93 reveals that ageing is associated with increasing transcription of main RPE-associated visual cycle genes (including LRAT, RPE65, RDH5, RDH10, RDH11; pathway enrichment BH-adjusted P = 4.6 × 10 ). This positive correlation is replicated in an independent set of 28 donors and a microarray dataset of 50 donors previously published. LRAT expression is positively regulated by retinoid by-products of the visual cycle (A2E and all-trans-retinal) involving modulation by retinoic acid receptor alpha transcription factor. The results substantiate a novel age-related positive feedback mechanism between accumulation of retinoid by-products in the RPE and the up-regulation of visual cycle genes.
衰老是对视网膜产生不利影响，是年龄相关性黄斑变性（AMD）的主要风险因素。我们报告了人类视网膜色素上皮（RPE）中与年龄相关的转录变化的首次 RNA-seq 分析，RPE 是 AMD 发病机制的主要部位。对年龄在 31 至 93 岁之间的人类供体的 RPE 进行全转录组测序，结果表明衰老与主要 RPE 相关视觉循环基因（包括 LRAT、RPE65、RDH5、RDH10、RDH11；途径富集 BH 调整后的 P 值=4.6×10）的转录增加有关。这一正相关在 28 个供体的独立数据集和以前发表的 50 个供体的微阵列数据集中得到了复制。LRAT 的表达受视觉循环的视黄醇副产物（A2E 和全反式视黄醛）的正向调节，涉及视黄酸受体α转录因子的调节。结果证实了 RPE 中视黄醇副产物的积累与视觉循环基因的上调之间存在新型的年龄相关正反馈机制。
