Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.
Department of Applied Chemistry, Kanagawa Institute of Technology, Kanagawa, Japan.
J Clin Invest. 2020 Oct 1;130(10):5370-5379. doi: 10.1172/JCI124070.
Chronic inflammation is deeply involved in various human disorders, such as cancer, neurodegenerative disorders, and metabolic disorders. Induction of epigenetic alterations, especially aberrant DNA methylation, is one of the major mechanisms, but how it is induced is still unclear. Here, we found that expression of TET genes, methylation erasers, was downregulated in inflamed mouse and human tissues, and that this was caused by upregulation of TET-targeting miRNAs such as MIR20A, MIR26B, and MIR29C, likely due to activation of NF-κB signaling downstream of IL-1β and TNF-α. However, TET knockdown induced only mild aberrant methylation. Nitric oxide (NO), produced by NOS2, enhanced enzymatic activity of DNA methyltransferases (DNMTs), methylation writers, and NO exposure induced minimal aberrant methylation. In contrast, a combination of TET knockdown and NO exposure synergistically induced aberrant methylation, involving genomic regions not methylated by either alone. The results showed that a vicious combination of TET repression, due to NF-κB activation, and DNMT activation, due to NO production, is responsible for aberrant methylation induction in human tissues.
慢性炎症深深涉及到各种人类疾病，如癌症、神经退行性疾病和代谢性疾病。表观遗传改变的诱导，特别是异常的 DNA 甲基化，是主要机制之一，但它是如何被诱导的仍然不清楚。在这里，我们发现，在炎症的小鼠和人类组织中，TET 基因（甲基化橡皮擦）的表达下调，这是由于 IL-1β 和 TNF-α 下游 NF-κB 信号的激活导致 TET 靶向 miRNA（如 MIR20A、MIR26B 和 MIR29C）的上调引起的。然而，TET 敲低仅诱导轻微的异常甲基化。一氧化氮（NO）由 NOS2 产生，增强了 DNA 甲基转移酶（DNMTs）的酶活性，甲基化写入器，NO 暴露诱导最小的异常甲基化。相比之下，TET 敲低和 NO 暴露的组合协同诱导异常甲基化，涉及到单独使用任一方法都不会甲基化的基因组区域。结果表明，由于 NF-κB 激活导致的 TET 抑制与由于 NO 产生导致的 DNMT 激活的恶性组合是导致人类组织中异常甲基化诱导的原因。
