染色体読者における機能獲得変異による細胞運命を損なう
Liling Wan1,2, Shasha Chong3,4, Fan Xuan5
1Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY, USA. Liling.Wan@Pennmedicine.upenn.edu.
Nature
|December 20, 2019
まとめ
ENLタンパク質の変異
科学分野:
- エピジェネティクス
- 癌 生物学
- 発達生物学
背景:
- ヒストンの改変は遺伝子発現を調節し,発達や病気において極めて重要です.
- 読者タンパク質はヒストンの改変を解釈しますが,疾患の病原性におけるその役割は不明です.
- ヒストンアセチル化のリーダであるENLタンパク質は,急性白血病とウィルムズ腫瘍に関与しています.
研究 の 目的:
- ENL YEATSドメインの変異がウィルムズ腫瘍の発達にどのように寄与するかを調査する.
- ENL変異がクロマチンの徴集と遺伝子発現に影響を与える分子メカニズムを解明する.
- 腫瘍形成におけるENL自己結合の役割を理解する.
主な方法:
- ヒトとマウスの細胞系を利用した
- クロマチンの免疫降水と遺伝子発現分析を行った.
- ネフロゲネシスの評価は ネズミの細胞測定を用いて行われました
- タンパク質の自己結合と核の点形成を研究した.
主要な成果:
- ENL変異は,クロマチンの徴集と転写制御における機能の獲得を与える.
- 変異性ENLは 遺伝子発現の変化を誘導し 癌前細胞の運命を好む
- ENL変異体は自己結合が増加し,クロマチンの占有率と遺伝子活性化を高める核点を形成する.
- ネフロゲネシスアッセイにおける変異性ENLは,ウィルムズ腫瘍に似た不分化構造を生成した.
結論:
- ENL YEATS領域のホットスポット変異は,発達中の正常な細胞運命を乱します.
- 変異によるENL自己結合は,自己強化されたクロマチンの徴集とウィルムズ腫瘍における腫瘍的結果につながります.
- これらのメカニズムを理解することで 小児腎臓がんの病原性について 洞察を得ることができます
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