DNAメチルトランスフェラーゼ遺伝子の標的型変異は,胚の致死性を引き起こす
1Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142.
Cell
|June 12, 1992
まとめ
遺伝子ターゲティングは,DNAメチルトランスフェラーゼが欠けているマウスを生み出した. 胚性幹細胞は生き残ったが,同卵性突然変異の胚は発達遅延と致死性を示し,DNAメチル化を示した.
科学分野:
- エピジェネティクスと遺伝子調節
- 発達生物学 発達生物学とは
- 遺伝学とゲノミクス
背景:
- DNAメチル化は哺乳類の発達に不可欠である.
- DNAメチルトランスフェラーゼ (DNMT) は,DNAメチル化に起因する主要な酵素である.
- DNMT in vivoの役割を理解することは,発達研究にとって不可欠です.
研究 の 目的:
- ノックアウトマウスモデルを作成することにより,DNAメチルトランスフェラーゼ (DNMT) のインビボ機能を調査する.
- 還元されたゲノムDNAメチレーションが胚の発達と細胞の生存能力に及ぼす影響を決定する.
主な方法:
- 胚性幹細胞 (ES) を標的とする遺伝子は,ネズミのDNAメチルトランスファーゼ遺伝子を破壊する.
- ホモジゴス型変異性ES細胞系を生成し,DNAメチルトランスファーゼ活性とDNAメチル化レベルを分析した.
- マウスの生殖系に突然変異を導入し,胚の死亡率と発達異常を評価する.
主要な成果:
- ホモジゴス型変異性ES細胞は,微量DNAメチルトランスフェラーゼ活性とゲノム内の5-メチルサイトシン (m5C) レベルが3倍に低下し,細胞の生存能力や形態学には影響はなかった.
- 南部ブラット分析は,変異性ES細胞における内生レトロウイルスDNAの脱メチル化を明らかにした.
- 遺伝子変異の生殖線伝播は,成長阻害,発達遅延,妊娠中期の胚死亡などのホモジゴス胚を産み出した.
- ホモジゴス胚は,ES細胞で観察されたように,m5Cレベルに同様の減少を示しました.
結論:
- ゲノムDNAメチル化の有意な減少は,胚性幹細胞の生存能力と適合する.
- しかし,胚の発達中のDNAメチル化の同様の減少は,重度の発達異常と致死性につながる.
- これらの発見は,哺乳類の胚形成におけるDNAメチル化の重要かつ文脈に依存する役割を強調しています.
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