Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.
Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100871, China.
Nucleic Acids Res. 2023 Feb 22;51(3):1087-1102. doi: 10.1093/nar/gkac1241.
Reactive oxygen species (ROS) are implicated in epithelial cell-state transition and deposition of extracellular matrix upon airway injury. Of the many cellular targets of ROS, oxidative DNA modification is a major driving signal. However, the role of oxidative DNA damage in modulation profibrotic processes has not been fully delineated. Herein, we report that oxidative DNA base lesions, 8-oxoG, complexed with 8-oxoguanine DNA glycosylase 1 (OGG1) functions as a pioneer factor, contributing to transcriptional reprogramming within airway epithelial cells. We show that TGFβ1-induced ROS increased 8-oxoG levels in open chromatin, dynamically reconfigure the chromatin state. OGG1 complexed with 8-oxoG recruits transcription factors, including phosphorylated SMAD3, to pro-fibrotic gene promoters thereby facilitating gene activation. Moreover, 8-oxoG levels are elevated in lungs of mice subjected to TGFβ1-induced injury. Pharmacologic targeting of OGG1 with the selective small molecule inhibitor of 8-oxoG binding, TH5487, abrogates fibrotic gene expression and remodeling in this model. Collectively, our study implicates that 8-oxoG substrate-specific binding by OGG1 is a central modulator of transcriptional regulation in response to tissue repair.
活性氧（ROS）参与上皮细胞状态转变以及气道损伤时细胞外基质的沉积。ROS 的许多细胞靶标中，氧化 DNA 修饰是主要的驱动信号。然而，氧化 DNA 损伤在调节成纤维过程中的作用尚未完全阐明。本研究报告称，与 8-氧鸟嘌呤 DNA 糖基化酶 1（OGG1）结合的氧化 DNA 碱基损伤 8-氧代鸟嘌呤（8-oxoG）作为启动子因子，参与气道上皮细胞内的转录重编程。研究表明，TGFβ1 诱导的 ROS 增加了开放染色质中 8-oxoG 的水平，动态地重新配置了染色质状态。与 8-oxoG 结合的 OGG1 募集转录因子，包括磷酸化的 SMAD3，到促纤维化基因启动子上，从而促进基因激活。此外，TGFβ1 诱导损伤的小鼠肺组织中 8-oxoG 水平升高。用 8-oxoG 结合的选择性小分子抑制剂 TH5487 对 OGG1 进行药理学靶向治疗，可阻断该模型中的纤维化基因表达和重塑。综上所述，本研究表明，OGG1 对 8-oxoG 底物的特异性结合是组织修复过程中转录调控的中心调节剂。
