TET repression and increased DNMT activity synergistically induce aberrant DNA methylation
Hideyuki Takeshima, … , Young-Joon Kim, Toshikazu Ushijima
Hideyuki Takeshima, … , Young-Joon Kim, Toshikazu Ushijima
Published July 14, 2020
Citation Information: J Clin Invest. 2020;130(10):5370-5379. https://doi.org/10.1172/JCI124070.
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Research Article Oncology

TET repression and increased DNMT activity synergistically induce aberrant DNA methylation

Abstract

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.

Authors

Hideyuki Takeshima, Tohru Niwa, Satoshi Yamashita, Takeji Takamura-Enya, Naoko Iida, Mika Wakabayashi, Sohachi Nanjo, Masanobu Abe, Toshiro Sugiyama, Young-Joon Kim, Toshikazu Ushijima

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Figure 3

Increased RELA binding levels at promoter regions of TET-targeting miRNAs.

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Increased RELA binding levels at promoter regions of TET-targeting miRNA...
(A) Activation of NF-κB signaling pathway in NUGC-3 cells by TNF-α. A downstream target gene of NF-κB signaling pathway, IL6, was upregulated by TNF-α treatment. Data represent mean ± SE. (B) Heatmap of RELA binding levels in NUGC-3 cells treated with TNF-α. RELA binding levels at genomic regions around TSSs of 44,112 transcripts were aligned according to the binding level after TNF-α treatment. Clear increase by the treatment was observed. Each row shows ± 2.5 kb centered on TSS. (C) Enriched motifs in RELA peaks detected in NUGC-3 cells treated with TNF-α. NF-κB binding motifs were most significantly enriched in NUGC-3 cells treated with TNF-α, showing successful detection of RELA binding sites. (D–F) RELA binding status around the putative promoter regions of TET-targeting miRNAs. RELA binding levels at putative promoter regions of MIR26B (CTDSP1) (D) and MIR20A (MIR17HG) (E) were robustly increased by TNF-α treatment. RELA binding levels at these host genes were comparable to that at the IL6 promoter (F). Black boxes indicate genomic regions with peaks detected. The y axis represents the read pileup normalized to the total number of reads at a base pair position (rpm/bp).