Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA.
Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA; Internal Medicine, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA; Sealy Center for Molecular Medicine, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA.
Redox Biol. 2018 Sep;18:43-53. doi: 10.1016/j.redox.2018.06.002. Epub 2018 Jun 12.
8-Oxoguanine DNA glycosylase 1 (OGG1) initiates the base excision repair pathway by removing one of the most abundant DNA lesions, 8-oxo-7,8-dihydroguanine (8-oxoG). Recent data showed that 8-oxoG not only is a pro-mutagenic genomic base lesion, but also functions as an epigenetic mark and that consequently OGG1 acquire distinct roles in modulation of gene expression. In support, lack of functional OGG1 in Ogg1 mice led to an altered expression of genes including those responsible for the aberrant innate and adaptive immune responses and susceptibility to metabolic disorders. Therefore, the present study examined stimulus-driven OGG1-DNA interactions at whole genome level using chromatin immunoprecipitation (ChIP)-coupled sequencing, and the roles of OGG1 enriched on the genome were validated by molecular and system-level approaches. Results showed that signaling levels of cellular ROS generated by TNFα, induced enrichment of OGG1 at specific sites of chromatinized DNA, primarily in the regulatory regions of genes. OGG1-ChIP-ed genes are associated with important cellular and biological processes and OGG1 enrichment was limited to a time scale required for immediate cellular responses. Prevention of OGG1-DNA interactions by siRNA depletion led to modulation of NF-κB's DNA occupancy and differential expression of genes. Taken together these data show TNFα-ROS-driven enrichment of OGG1 at gene regulatory regions in the chromatinized DNA, which is a prerequisite to modulation of gene expression for prompt cellular responses to oxidant stress.
8-氧鸟嘌呤 DNA 糖基化酶 1（OGG1）通过切除最丰富的 DNA 损伤之一 8-氧-7,8-二氢鸟嘌呤（8-oxoG）来启动碱基切除修复途径。最近的数据表明，8-oxoG 不仅是一种促突变的基因组碱基损伤，而且还作为一种表观遗传标记，因此 OGG1 在调节基因表达方面具有不同的作用。支持这一观点的是，Ogg1 基因敲除小鼠中缺乏功能性 OGG1 导致包括负责异常先天和适应性免疫反应以及易患代谢紊乱的基因表达发生改变。因此，本研究使用染色质免疫沉淀（ChIP）结合测序在全基因组水平上检查了刺激驱动的 OGG1-DNA 相互作用，并通过分子和系统水平的方法验证了基因组中 OGG1 富集的作用。结果表明，TNFα 产生的细胞 ROS 信号水平诱导 OGG1 特异性富集在染色质化 DNA 的特定部位，主要是在基因的调控区域。OGG1-ChIP 富集的基因与重要的细胞和生物学过程相关，OGG1 富集的时间范围限于即刻细胞反应所需的时间尺度。通过 siRNA 耗尽防止 OGG1-DNA 相互作用导致 NF-κB 的 DNA 占据和基因表达的差异。总之，这些数据表明，TNFα-ROS 驱动 OGG1 在染色质化 DNA 的基因调控区域富集，这是氧化应激引起的即刻细胞反应中调节基因表达的前提。
