Photooxidation of A2E by Blue Light Regulates Heme Oxygenase 1 Expression via NF-κB and Lysine Methyltransferase 2A in ARPE-19 Cells

Background: 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 (HMOX1) 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 HMOX1 by A2E and BL. Methods: 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 HMOX1 transcription. Clinical transcriptome data were used to evaluate HMOX1 expression in patients with age-related macular degeneration (AMD). Results: In ARPE-19 cells, the expression of HMOX1, 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 HMOX1 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 HMOX1 promoter, and, subsequently, HMOX1 expression. The retinal tissues of patients with late-stage AMD showed significantly increased expression of HMOX1 compared to normal retinal tissues. In addition, the expression levels of MLL1 and HMOX1 in retinal tissues were correlated. Conclusions: Taken together, our results suggest that BL induces HMOX1 expression by activating NF-κB and MLL1 in RPE cells.