クロマチン修飾酵素は,再プログラミングの調節剤として作用する.
Tamer T Onder1, Nergis Kara, Anne Cherry
1Stem Cell Transplantation Program, Division of Pediatric Hematology and Oncology, Manton Center for Orphan Disease Research, Children's Hospital Boston and Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Nature
|March 6, 2012
まとめ
研究者らは,誘発性多能幹細胞 (iPSC) 生成に影響を与える特定のクロマチンの修飾酵素を特定しました. ヒストンメチルトランスフェラーゼであるDOT1Lを阻害することで,再プログラムが加速され,iPSCの収穫量が増加し,効率的なiPSC生産のための新しい戦略を提供しました.
科学分野:
- エピジェネティクスと幹細胞生物学
- クロマチンの改変と遺伝子調節
- 細胞の再プログラムメカニズム
背景:
- 誘発性多能幹細胞 (iPSCs) への体細胞再プログラムには,広範な表遺伝子改造が含まれています.
- この過程における特定のクロマチンを修飾する酵素の役割は完全に理解されていません.
- 重要な規制者を特定することで,iPSCの発電効率を最適化することができます.
研究 の 目的:
- クロマチンを修飾する酵素が誘発性多能幹細胞 (iPSC) 生成の効率にどのように影響するかを調査する.
- 再プログラムプロセスにおける障壁や促進剤として作用する特定の酵素を特定する.
- 標的型表遺伝子変調を用いたiPSC生産の強化のための戦略を探求する.
主な方法:
- 短いヘアピンRNA (shRNA) を利用して,DNAとヒストンのメチル化経路にある遺伝子を標的にした.
- 様々な染色体調節酵素を抑制することで,iPSC生成効率に及ぼす影響を評価した.
- 再プログラム中のH3K79二メチル化 (H3K79me2) 分布の全ゲノム分析を行った.
主要な成果:
- EZH2を含むポリコンブ抑制複合体1および2の成分を阻害すると,再プログラム効率が低下する.
- SUV39H1,YY1,DOT1Lの強化再プログラミングを抑制する.
- DOT1L阻害は再プログラムを加速し,iPSCの収量を増やし,KLF4とc-Mycを代用し,NANOGとLIN28レベルの増加と相関しています.
結論:
- 特定のクロマチンの修飾酵素は,体細胞の再プログラムにおけるバリアやファシリテーターとして重要な役割を果たします.
- DOT1L阻害は,iPSCの発電効率と生産性を高める強力な戦略として浮上しています.
- クロマチンの改変経路をターゲットにすることで,再プログラム因子数が少なくて,iPSCの生産を改善するための有望なアプローチが提供されます.
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