title: Regulation of aryl hydrocarbon receptor-mediated transcription in human retinal pigmented epithelial cells.
abstract: The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor with pleiotropic effects in normal physiology or vascular development, xenobiotic metabolism, and cancer. A previous study has reported that BRG1, a component of the SWI/SNF complex, is a coactivator for AHR and is recruited to the promoter region of the CYP1A1 gene in mouse hepatocytes. Recent data suggest that AHR is also expressed in human retinal pigment epithelial cells (ARPE-19), which play a crucial role in retinal physiology and the visual cycle. Multiple studies have shown that the AHR plays an important role in the pathogenesis of retinal diseases including age-related macular degeneration. However, the mechanism of AHR transcriptional activation in retinal pigment cells has not been reported. Here, we demonstrate that the AHR signaling pathway is active in ARPE-19 cells, as in hepatocytes, but with different target gene specificity. We also found that chromatin remodeling by the BRG1-containing SWI/SNF complex is required for the AHR-mediated expression of target genes in ARPE-19 cells. We identified a novel enhancer region (-12 kb) of the CYP1A1 gene in ARPE-19 cells, to which both AHR and BRG1 are recruited in a ligand-dependent manner. BRG1 is associated with the AHR in ARPE-19 cells, and the C-terminal activation domain of the AHR directly interacts with BRG1. Furthermore, depletion of BRG1 caused a reduction in chromatin accessibility at the CYP1A1 enhancer. These results suggest that ARPE-19 cells possess an AHR-mediated transcription pathway with different target gene specificity, and that BRG1 is required for AHR-mediated transcription in ARPE-19 cells.
authors.affiliation: Gachon Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon 406-799, Republic of Korea.
authors.forename: Hong Lan
authors.initials: HL
authors.lastname: Jin
authors.affiliation: Gachon Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon 406-799, Republic of Korea. Electronic address: kwjeong@gachon.ac.kr.
authors.forename: Kwang Won
authors.initials: KW
authors.lastname: Jeong
mesh_terms: D002460:Cell Line; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D004265:DNA Helicases / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D056945:Hep G2 Cells; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics*; D055213:Retinal Pigment Epithelium / Q000166:cytology* / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000502:physiology; D015533:Transcriptional Activation / Q000502:physiology*
chemical_list: D009687:Nuclear Proteins; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; C569463:CYP1A1 protein, human; D019363:Cytochrome P-450 CYP1A1; C084108:SMARCA4 protein, human; D004265:DNA Helicases
keywords: AMD; ARPE-19; Aryl hydrocarbon receptor; BRG1