TET媒介のDNA脱メチル化は,レフティ・ノダルのシグナリングを調節することによって,ガストルレーションを制御する
Hai-Qiang Dai1,2, Bang-An Wang1,2, Lu Yang3,4
1State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Nature
|October 28, 2016
まとめ
マウスの10−11転位 (TET) 遺伝子不活性化により,DNAメチル化と脱メチル化が妨げられ,初期胚形成の際にノード信号伝達に影響を及ぼします.
科学分野:
- エピジェネティクスと発達生物学
- 哺乳類の胚形成
- DNAメチル化ダイナミクス
背景:
- 哺乳類のゲノムには,DNAメチルトランスフェラーゼ (DNMTs) によるサイトシンメチル化のような表遺伝的変化がある.
- 10−11 転位 (TET) ダイオキシゲナーゼによる5-メチルシトシンの酸化が脱メチル化を媒介する.
- マウスの胚形成におけるDNAメチル化と脱メチル化の正確な役割については,さらなる解明が必要である.
研究 の 目的:
- マウスの胚形成におけるTET媒介DNA脱メチル化の機能的意義を調査する.
- 胚のシグナル伝達経路とDNAメチル化ダイナミクスを結びつける分子メカニズムを解明する.
主な方法:
- 活性化されていないTet遺伝子 (Tet null変異体) を有するマウスの生成と分析.
- 胚のフェノタイプの評価,ガストルレーションとメソデームの発達を含む.
- ノダル,レフティ,DNAメチルトランスフェラーゼ (DNMT) の遺伝子発現とメチル化パターンの分子分析.
主要な成果:
- TETの無活性化により 胃細胞の欠陥,原始的な線状パターンの異常,およびメソデームの成熟が損なわれた.
- これらのフェノタイプは,ノダルシグナル伝達が強化された胚を模倣し,ノダル変異によって部分的に救出されました.
- Tet欠乏症は,DNAメチル化が増加したLefty遺伝子の発現を減少させ,DNMT3A/3Bを阻害することで,これらの欠陥を回復させました.
結論:
- TET媒介による5メチルサイトシンの酸化は,胚形成中のレフティ・ノダルのシグナリングの調節に不可欠である.
- TETとDNMTsによってバランスをとったダイナミックなDNAメチル化と脱メチル化は,早期のボディプラン形成に不可欠です.
- エピジェネティックバランスが崩れると 重要な信号伝達経路が変化し 発達異常が生じます
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