Screen and functional analysis of epigenetic factors that regulate cellular senescence
Project/Area Number |
17H06969
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Research Category |
Grant-in-Aid for Research Activity Start-up
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Allocation Type | Single-year Grants |
Research Field |
Tumor biology
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Research Institution | Kumamoto University |
Principal Investigator |
Tanaka Hiroshi 熊本大学, 発生医学研究所, 特定事業研究員 (20802127)
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Project Period (FY) |
2017-08-25 – 2019-03-31
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Project Status |
Completed (Fiscal Year 2018)
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Budget Amount *help |
¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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Keywords | 細胞老化 / 老化 / エピジェネティクス / ヒストン修飾 / ミトコンドリア |
Outline of Final Research Achievements |
Senescent cells exhibit higher mitochondrial activities compared with proliferating cells, which contributes to the production and secretion of senescence-associated secretory proteins. The researchers performed gene-knockdown screen and revealed that depletion of SETD8 or NSD2 histone methyltransferase cause senescence and senescence-associated abnormal activation of mitochondrial respiration. Mechanistically, depletion of SETD8 decreased the levels of histone H4 lysine 20 mono-methylation at p16 and p21 gene loci and activated their expression. Then, p16 and p21 activated retinoblastoma protein (RB) to enhance mitochondrial respiration. Loss of NSD2 also activated p21 and RB to induce senescence. In summary, our data revealed that multiple epigenetic regulators contribute to preventing senescence and senescence-associated metabolic remodeling by maintaining p16/p21-RB pathway.
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Academic Significance and Societal Importance of the Research Achievements |
細胞の遺伝子の働きは、ゲノムDNAやヒストンなどのタンパク質に対するメチル化などの化学修飾により制御されている。興味深いことに、これらの化学修飾(エピゲノム)は可逆的に調節することができる。本研究により、細胞の老化過程に寄与するエピゲノム制御遺伝子が明らかになった。本研究成果は、今後、老化速度の制御や、老化に付随するガン、肥満・糖尿病、ならびに神経変性疾患などの発症メカニズムの解明ならびに予防・治療法の開発につながることが期待される。
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Report
(3 results)
Research Products
(2 results)