Clarification of molecular mechanism of aberrant DNA methylation induction by chronic inflammation
| Project/Area Number |
15H04302
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Tumor biology
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| Research Institution | National Cancer Center Japan |
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Principal Investigator |
Ushijima Toshikazu 国立研究開発法人国立がん研究センター, 研究所, 分野長 (90232818)
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| Co-Investigator(Kenkyū-buntansha) |
前田 将宏 国立研究開発法人国立がん研究センター, 研究所, 研究員 (30738703)
竹内 由佳 (並木由佳) 国立研究開発法人国立がん研究センター, 研究所, 研究員 (20590417)
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| Project Period (FY) |
2015-04-01 – 2018-03-31
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| Project Status |
Completed (Fiscal Year 2017)
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| Budget Amount *help |
¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000)
Fiscal Year 2017: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2016: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2015: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
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| Keywords | エピジェネティクス |
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| Outline of Final Research Achievements |
Analysis of dysregulation of DNA methylation machineries revealed 1) that Tet methylcytosine dioxygenases (Tet) genes, Tet1, Tet2, and Tet3, were repressed by NF-kB signaling, downstream of IL-1β and TNF-α, via up-regulation of specific miRNAs, such as miR-26b and miR-29c, and 2) that exposure to nitric oxide, produced by Nos2, enhanced enzymatic activity of DNA methyltransferases (DNMTs). In cultured cells, TET repression by overexpression of one of the identified miRNAs did not induce aberrant DNA methylation, while triple knockout of all the three TET genes induced aberrant DNA methylation at thousands of genomic loci. The number of hypermethylated loci became larger in combination with exposure to nitric oxide. These results suggested that, in human tissues, a vicious combination of TET repression and increased DNMT activity biologically induce aberrant DNA methylation.
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Report
(4 results)
Research Products
(17 results)
