Gachon Research Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon 406-799, Korea.
Curr Issues Mol Biol. 2021 Oct 16;43(3):1623-1631. doi: 10.3390/cimb43030115.
Aryl hydrocarbon receptors (AHRs), a class of ligand-dependent nuclear receptors that regulate cellular responses by inducing the expression of various target genes in response to external signals, are implicated in maintaining retinal tissue homeostasis. Previous studies have shown that the regulation of AHR-induced gene expression requires transcriptional co-regulators. However, it is not yet clear how chromatin remodelers, histone methyltransferases and coactivators interact during AHR-mediated gene expression in human retinal cells. In this study, we reveal that the histone methyltransferase MLL1 and the coactivator FLII are involved in AHR-mediated gene expression in retinal pigment epithelial cells. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) significantly increased the expression of and in ARPE-19 cells, whereas FLII or MLL1 depletion significantly reduced the expression of these genes induced by TCDD. Mechanistically, FLII binds to AHR in a ligand-dependent manner in ARPE-19 cells. In particular, the binding of FLII to MLL1 occurs through the GelB domain of FLII. In addition, MLL1 binds to AHR in a ligand-independent manner. FLII is involved in the recruitment of the BRG1 chromatin remodeler and MLL1 histone methyltransferase to the AHR-regulated gene region in ARPE-19 cells and consequently, plays an important role in RNA polymerase II binding and transcriptional activity by modulating chromatin accessibility. Our results identify the functions and mechanisms of action of FLII and MLL1 in AHR-induced gene expression in human retinal pigment epithelial cells.
芳烃受体（AHRs）是一类配体依赖性核受体，通过诱导各种靶基因的表达来响应外部信号，从而调节细胞反应，参与维持视网膜组织的内稳态。先前的研究表明，AHR 诱导的基因表达的调节需要转录共调节剂。然而，目前尚不清楚染色质重塑酶、组蛋白甲基转移酶和共激活因子在人视网膜细胞中 AHR 介导的基因表达过程中是如何相互作用的。在这项研究中，我们揭示了组蛋白甲基转移酶 MLL1 和共激活因子 FLII 参与了视网膜色素上皮细胞中 AHR 介导的基因表达。2,3,7,8-四氯二苯并对二恶英（TCDD）显著增加了 ARPE-19 细胞中 和 的表达，而 FLII 或 MLL1 的耗竭显著降低了 TCDD 诱导的这些基因的表达。在机制上，FLII 在 ARPE-19 细胞中以配体依赖的方式与 AHR 结合。特别是，FLII 通过 FLII 的 GelB 结构域与 MLL1 结合。此外，MLL1 以配体非依赖的方式与 AHR 结合。FLII 参与了 BRG1 染色质重塑酶和 MLL1 组蛋白甲基转移酶在 AHR 调节的 ARPE-19 细胞中 基因区域的募集，从而通过调节染色质可及性在 RNA 聚合酶 II 结合和转录活性中发挥重要作用。我们的研究结果确定了 FLII 和 MLL1 在人视网膜色素上皮细胞中 AHR 诱导的基因表达中的功能和作用机制。
