SIRT1は,ヘテロクロマチン形成中にヒストンメチルトランスファーゼSUV39H1を調節する
Alejandro Vaquero1, Michael Scher, Hediye Erdjument-Bromage
1Howard Hughes Medical Institute, Division of Nucleic Acids Enzymology, Department of Biochemistry, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Jersey 08854, USA.
Nature
|November 16, 2007
まとめ
選択的ヘテロクロマチンの形成を促進し,ヒストン脱酸化酵素SIRT1はメチルトランスファーゼSUV39H1.1を直接標的にして脱酸化させます. この相互作用により,SUV39H1の活性が強化され,H3K9me3のレベルが上昇し,ヘテロクロマチンタンパク質1の局所化に影響を与えます.
科学分野:
- エピジェネティクスとクロマチン生物学
- 遺伝子調節の分子メカニズム
背景:
- 選択性ヘテロクロマチンは,構成性ヘテロクロマチンやユークロマチンとは異なり,遺伝子転写を動的に調節する.
- シルトゥイン1 (SIRT1) とバリエーション3-9ホモログ1 (SUV39H1) の抑制剤は,選択的ヘテロクロマチン形成における重要な酵素である.
- SUV39H1は,ヘテロクロマチンの特徴であるH3K9me3を触媒化し,SIRT1はヒストンH4を脱酸化し,H3K9me3レベルに影響を与える.
研究 の 目的:
- SIRT1がH3K9me3レベルに影響を与える分子メカニズムを解明する.
- SIRT1とSUV39H1.1.の間の直接的な相互作用と機能的関係を調査する.
- SIRT1がSUV39H1の活性と,ヘテロクロマチン形成におけるその役割をどのように調節するかを理解する.
主な方法:
- SIRT1とSUV39H1.1.の間の直接的な相互作用を証明するための生化学的分析.
- in vitroおよびin vivo実験で,SIRT1脱酸化がSUV39H1活動に及ぼす影響を評価する.
- H3K9me3レベルと,SIRT1.1の存在と欠如におけるヘテロクロマチンタンパク質1の局所化に関する分析.
主要な成果:
- SIRT1は,その触媒SETドメイン内のライシン266でSUV39H1と直接相互作用し,採用し,脱酸化します.
- SIRT1媒介によるSUV39H1の脱エチル化により,メチルトランスフェラーゼの活性が強化され,H3K9me3.3が増加します.
- SIRT1機能の喪失は,SUV39H1依存のH3K9me3の蓄積とヘテロクロマチンタンパク質1の局所化を損なう.
結論:
- SIRT1は脱エチル化によって,ヘテロクロマチン関連メチルトランスフェラーゼSUV39H1の活性を直接調節する.
- SIRT1とSUV39H1の間のこの機能的なリンクは,H3K9me3レベルと選択的ヘテロクロマチンを制御するための新しいメカニズムを提供します.
- この発見は,表遺伝子遺伝子の遺伝子調節におけるヒストンの脱酸化とメチル化の間の重要な相互作用を強調しています.
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