Abstract：
The transcription factor NRF2 plays a pivotal role in maintaining redox and metabolic homeostasis by orchestrating oxidative stress-dependent transcription programs. Despite growing evidence implicating various cellular components in the regulation of NRF2 activity at the posttranslational stage, relatively less is known about the factors dictating the transcriptional activation of NRF2 in response to oxidative stress. In this study, we report the crucial roles of MLL1, an H3K4-specific methyltransferase, and UTX, an H3K27-specific histone demethylase, in the NRF2-dependent transcription program under oxidative stress. We find that the depletion of MLL1 or UTX results in increased susceptibility to oxidative stress, accompanied by higher intracellular ROS and the failed activation of antioxidant genes, including NRF2. In addition, MLL1 and UTX selectively target the NRF2 promoter, and exogenous FLAG-NRF2 expression increases the viability of MLL1-or UTX-depleted cells upon exposure to hydrogen peroxide. RNA-seq analysis demonstrates that depletion of MLL1 or UTX affects the changes in NRF2-dependent transcriptome in response to oxidative stress. Furthermore, ChIP and ChIP-seq analyses find that MLL1 and UTX functionally cooperate to establish a chromatin environment that favors active transcription at the H3K4me3/H3K27me3 bivalent NRF2 promoter in response to ROS-induced oxidative stress. Collectively, these findings provide a molecular mechanism underlying the cellular response to oxidative stress and highlight the importance of the chromatin structure and function in maintaining redox homeostasis.
摘要：
转录因子NRF2通过协调氧化应激依赖性转录程序在维持氧化还原和代谢稳态中起关键作用。尽管越来越多的证据表明，在翻译后阶段，各种细胞成分参与了NRF2活性的调节，对氧化应激反应中决定NRF2转录激活的因素的了解相对较少。在这项研究中,我们报道了MLL1的关键作用，MLL1是一种H3K4特异性甲基转移酶，和UTX，一种H3K27特异性组蛋白去甲基酶，在氧化应激下NRF2依赖性转录程序中。我们发现MLL1或UTX的消耗导致对氧化应激的敏感性增加，伴随着较高的细胞内ROS和抗氧化基因的失败激活，包括NRF2。此外,MLL1和UTX选择性靶向NRF2启动子，和外源FLAG-NRF2表达增加MLL1或UTX耗尽的细胞在暴露于过氧化氢时的活力。RNA-seq分析表明MLL1或UTX的消耗影响响应于氧化应激的NRF2依赖性转录组的变化。此外，ChIP和ChIP-seq分析发现，MLL1和UTX在功能上合作建立了一个染色质环境，该环境有利于响应ROS诱导的氧化应激而在H3K4me3/H3K27me3二价NRF2启动子处进行主动转录。总的来说，这些发现提供了细胞对氧化应激反应的分子机制，并强调了染色质结构和功能在维持氧化还原稳态中的重要性。
