Shin Chae Young, Jeong Kwang Won
Gachon Research Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon 21936, Korea.
Life (Basel). 2022 Oct 25;12(11):1698. doi: 10.3390/life12111698.
N-retinylidene-N-retinylethanolamine (A2E) is a component of drusen that accumulates in retinal cells and induces oxidative stress through photooxidation, such as blue light (BL). We found that the heme oxygenase 1 () gene responds sensitively to photooxidation by the BL of A2E in retinal pigment epithelial (RPE) cells, and we sought to identify the transcription factors and coactivators involved in the upregulation of by A2E and BL. A2E-laden human RPE cells (ARPE-19) were exposed to BL (430 nm). RNA sequencing was performed to identify genes responsive to BL exposure. Chromatin immunoprecipitation and RT-qPCR were performed to determine the regulation of transcription. Clinical transcriptome data were used to evaluate expression in patients with age-related macular degeneration (AMD). In ARPE-19 cells, the expression of , one of the NF-κB target genes, was significantly increased by A2E and BL. The binding of RELA and RNA polymerase II to the promoter region of was significantly increased by A2E and BL. Lysine methyltransferase 2A (MLL1) plays an important role in H3K4me3 methylation, NF-κB recruitment, chromatin remodeling at the promoter, and, subsequently, expression. The retinal tissues of patients with late-stage AMD showed significantly increased expression of compared to normal retinal tissues. In addition, the expression levels of and in retinal tissues were correlated. Taken together, our results suggest that BL induces expression by activating NF-κB and MLL1 in RPE cells.
N-视黄叉基-N-视黄基乙醇胺（A2E）是玻璃膜疣的一种成分，它在视网膜细胞中蓄积，并通过光氧化作用（如蓝光）诱导氧化应激。我们发现血红素加氧酶1（）基因对视网膜色素上皮（RPE）细胞中A2E的蓝光光氧化作用反应敏感，我们试图确定参与A2E和蓝光上调的转录因子和共激活因子。将负载A2E的人RPE细胞（ARPE-19）暴露于蓝光（430nm）。进行RNA测序以鉴定对蓝光暴露有反应的基因。进行染色质免疫沉淀和RT-qPCR以确定转录调控。使用临床转录组数据评估年龄相关性黄斑变性（AMD）患者中的表达。在ARPE-19细胞中，NF-κB靶基因之一的表达通过A2E和蓝光显著增加。RELA和RNA聚合酶II与启动子区域的结合通过A2E和蓝光显著增加。赖氨酸甲基转移酶2A（MLL1）在H3K4me3甲基化、NF-κB募集、启动子处的染色质重塑以及随后的表达中起重要作用。晚期AMD患者的视网膜组织与正常视网膜组织相比，表达显著增加。此外，视网膜组织中的和表达水平相关。综上所述，我们的结果表明蓝光通过激活RPE细胞中的NF-κB和MLL1诱导表达。
