TET repression and increased DNMT activity synergistically induce aberrant DNA methylation
| Autor: | Sohachi Nanjo, Masanobu Abe, Naoko Iida, Tohru Niwa, Mika Wakabayashi, Takeji Takamura-Enya, Toshikazu Ushijima, Young Joon Kim, Satoshi Yamashita, Hideyuki Takeshima, Toshiro Sugiyama |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Methyltransferase Down-Regulation Nitric Oxide Dioxygenases Epigenesis Genetic Helicobacter Infections Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Downregulation and upregulation microRNA Animals Humans Epigenetics DNA Modification Methylases Psychological repression Inflammation Gene knockdown Helicobacter pylori Chemistry NF-kappa B General Medicine Methylation DNA Methylation Up-Regulation Mice Inbred C57BL Disease Models Animal MicroRNAs 030104 developmental biology Gastritis 030220 oncology & carcinogenesis Cancer research Helicobacter felis DNA Research Article |
| Zdroj: | J Clin Invest |
| ISSN: | 1558-8238 0021-9738 |
| DOI: | 10.1172/jci124070 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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