Mechanism of epigenetic regulation by nitric oxide with a novel compound regulating the modification of cysteine residue
| Project/Area Number |
18H02579
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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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| Review Section |
Basic Section 47040:Pharmacology-related
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| Research Institution | Okayama University |
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Principal Investigator |
Uehara Takashi 岡山大学, 医歯薬学総合研究科, 教授 (00261321)
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| Co-Investigator(Kenkyū-buntansha) |
竹内 靖雄 岡山大学, 医歯薬学総合研究科, 教授 (00163387)
伊藤 昭博 東京薬科大学, 生命科学部, 教授 (40391859)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2020: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2019: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2018: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
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| Keywords | 一酸化窒素 / エピジェネティクス / 遺伝子発現 / エピゲノム / ニトロシル化 / S-ニトロシル化 / 細胞死 / 阻害薬 / 神経細胞死 / パーキンソン病 |
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| Outline of Final Research Achievements |
We clarified that several enzymes involved in epigenetics are targets of nitric oxide (NO). We found that the enzymatic activity was significantly inhibited by modification of Cys residue. In addition, we screened the genes whose expression levels were changed by NO exposure with RNA-seq analysis. From this screening, we succeeded in isolating many candidate genes. Then, we attempted to isolate the compound that attenuates the modification from in silico screening. A compound could inhibit S-nitrosylation of target protein in a concentration-dependent manner. Furthermore, this chemical significantly attenuated the gene expression in response to NO.
Our findings strongly suggested that NO is a key factor that regulates gene expression via dysfunction of epigenetic system.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究は生体内で産生されるガス状分子である一酸化窒素（NO）の遺伝子発現に対する影響を調べたものである．一酸化窒素は，血圧調節や記憶形成など様々な役割を担っている．この研究で，NOがある酵素に結合・修飾することで活性を低下させ，ゲノム修飾を抑制して遺伝子発現を誘導することが明らかとなった．さらに，この修飾を特異的に阻害する化合物の単離に成功した．この化合物はNOによる遺伝子発現を顕著に抑制することが確認された．また，NOによって形成されるがんに有効であった．従って，がんや神経変性疾患の中，ある種のものはNOが原因であり，本研究で開発された化合物は強力なツールであることが示唆された．
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Report
(4 results)
Research Products
(28 results)
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[Journal Article] Spatiotemporal analysis of the UPR transition induced by methylmercury in the mouse brain.2021
Author(s)
Hiraoka, H., Nomura, R., Takasugi, N., Akai, R., Iwawaki, T., Kumagai, Y., Fujimura, M., and Uehara, T.
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Journal Title
Arch. Toxicol.
Volume: 95
Issue: 4
Pages: 1241-1250
DOI
NAID
Related Report
Peer Reviewed / Open Access
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[Journal Article] Emerging role of electrophiles as a key regulator for endoplasmic reticulum (ER) stress.2019
Author(s)
Takasugi, N., Hiraoka, H., Nakahara, K., Akiyama, S., Fujikawa, K., Nomura, R., Furuichi, M., and Uehara, T.
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Journal Title
Int. J. Mol. Sci.
Volume: 20(7)
Issue: 7
Pages: 1783-1783
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] MITOL prevemts ER stress-induced apoptosis by IRE1 ubiquitylation at mitochondrial-ER contact sites.2019
Author(s)
Takeda, K., Nagashima, S., Shiiba, I., Uda, A., Tokuyama, T., Ito, N., Fukuda, T., Matsushita, N., Ishido, S., Iwawaki, T., Uehara, T., Inatome, R., and Yanagi, S.
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Journal Title
EMBO J.
Volume: 38
Issue: 15
DOI
Related Report
Peer Reviewed / Open Access
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[Book] 実験医学2020
Author(s)
中原健吾，上原 孝
Total Pages
5
Publisher
羊土社
Related Report
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[Book] 実験医学2018
Author(s)
高杉展正，上原 孝
Total Pages
6
Publisher
羊土社
Related Report
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[Book] 脳神経化学2018
Author(s)
奥田洸作，高杉展正，上原 孝
Total Pages
10
Publisher
化学同人
Related Report
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