哺乳類のゲノムにおけるDNAメチル化の編集
X Shawn Liu1, Hao Wu1, Xiong Ji1
1Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Cell
|September 24, 2016
まとめ
研究者は,dCas9とTet1またはDnmt3aを融合した新しいDNAメチレーション編集ツールを開発しました. これらのエピジェネティック・エディティング・ツールは,マウスで実証された応用で,DNAメチル化をターゲットにすることで,精密に遺伝子発現を制御します.
科学分野:
- エピジェネティクスと分子生物学
- 遺伝子規制
- ゲノム工学
背景:
- 哺乳類のDNAメチル化は 遺伝子発現を制御する重要な表遺伝子機構である.
- 特定のDNAメチル化部位の機能的影響を調査することは大きな課題です.
研究 の 目的:
- 標的型DNAメチレーション編集システムを開発し,検証する.
- DNAメチル化パターンを正確に変化させる能力と 遺伝子発現への下流効果を実証する.
主な方法:
- 触媒的に無効なCas9 (dCas9) とTet1またはDnmt3a酵素の融合
- dCas9-Tet1またはdCas9-Dnmt3aを,プロモーターおよび強化剤を含む特定のゲノムロシにターゲットにする.
- DNAメチル化,遺伝子発現,タンパク質結合の変化を標的の編集に反応して評価する.
主要な成果:
- dCas9-Tet1またはdCas9-Dnmt3aの標的投与により,それぞれ正確なDNA脱メチル化またはメチル化が可能になりました.
- dCas9- Tet1はニューロンにおけるBDNF発現と細胞再プログラムのためのMyoD活性化を媒介した.
- dCas9-Dnmt3aはCTCF結合とDNAループを妨害することで遺伝子発現を変化させた.
結論:
- dCas9融合システムは,標的型DNAメチレーション編集のための強力なプラットフォームを提供します.
- これらのツールは,マウスモデルを含む様々な生物学的文脈における表遺伝子調節の機能研究を容易にする.
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