TET repression and increased DNMT activity synergistically induce aberrant DNA methylation
TET repression and increased DNMT activity synergistically induce aberrant DNA methylation
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DOI：
10.1172/jci124070
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发表时间：
2020-10-01
影响因子：
15.9
通讯作者：
Ushijima, Toshikazu
中科院分区：
文献类型：
--
作者：
Takeshima, Hideyuki;Niwa, Tohru;Ushijima, Toshikazu
慢性炎症与各种人类疾病如癌症、神经退行性疾病和代谢疾病密切相关。表观遗传学改变的诱导，尤其是异常的DNA甲基化，是主要的机制之一，但它是如何被诱导的仍然不清楚。在此，我们发现泰特基因（甲基化清除剂）的表达在发炎的小鼠和人体组织中下调，这是由靶向TET的miRNA（如MIR 20 A、MIR 26 B和MIR 29 C）上调引起的，可能是由于IL-1 β和TNF-α下游的NF-κ B信号转导激活所致。然而，泰特敲低仅诱导轻度异常甲基化。由NOS 2产生的一氧化氮（NO）增强了DNA甲基转移酶（DNMT）的酶活性，甲基化作家，NO暴露诱导最小的异常甲基化。相比之下，泰特敲除和NO暴露的组合协同诱导异常甲基化，涉及单独不甲基化的基因组区域。结果表明，由于NF-κ B激活而导致的泰特抑制和由于NO产生而导致的DNMT激活的恶性组合是人体组织中异常甲基化诱导的原因。
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-kappa B signaling downstream of IL-1 beta and TNF-alpha. 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-kappa B activation, and DNMT activation, due to NO production, is responsible for aberrant methylation induction in human tissues.