Clr4 (Suv39h) の自動メチル化誘発型スイッチは表遺伝的安定性を維持する
Nahid Iglesias1,2, Mark A Currie1,2, Gloria Jih1,2
1Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
Nature
|July 28, 2018
まとめ
研究者は,H3K9メチルトランスフェラーゼClr4が本質的に抑制され,自動的に活性化される方法を発見しました. この調節は異常な遺伝子の静止を防止し,ヒトに保存されるメカニズムである表遺伝子の安定性を維持します.
科学分野:
- エピジェネティクス
- 分子生物学
- 遺伝子規制
背景:
- ヒストンH3ライシン9メチル化 (H3K9me) は,遺伝子静止とゲノム安定性にとって極めて重要です.
- H3K9メチルトランスフェラーゼは,陽性フィードバックループを通じてヘテロクロマチンを確立し維持する.
- H3K9メチルトランスフェラーゼの活動を制限するメカニズムは完全に理解されていません.
研究 の 目的:
- H3K9メチルトランスフェラーゼClr4の自己抑制および自己活性化メカニズムを調査する.
- 異変性ヘテロクロマチンの形成を防ぐためにClr4の活性がどのように調節されるかを理解する.
- エピジェネティックの安定性を維持する 内在の調節の役割を調査する.
主な方法:
- 酵素活性の研究のための生化学的測定法
- 酵素構造を決定するX線結晶学
- 制御ループの機能を評価するサイト指向型変異.
主要な成果:
- Clr4は,基質結合ポケットをブロックする内部ループにより,自己抑制された形状に存在する.
- ループ内のライシンの自動メチル化により,コンフォームスイッチが起動し,Clr4の活性が強化されます.
- この調節を妨げる突然変異は,異常なH3K9me,ヘテロクロマチンの喪失,および成長障害を引き起こす.
結論:
- 精密なH3K9メチル化には,Clr4の内在的抑制と自己活性化が不可欠である.
- この調節メカニズムは表遺伝子の不安定性と異常な遺伝子静止を防止します
- この自己抑制メカニズムは,ヒトの同種を含む他のH3K9メチルトランスファーゼに保存されます.
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