合成後の翻訳変化:原生クロマチンの化学触媒駆動型地域選択ヒストンアサイレーション
Yoshifumi Amamoto1,2, Yuki Aoi1,2, Nozomu Nagashima1
1Graduate School of Pharmaceutical Sciences, The University of Tokyo , 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Journal of the American Chemical Society
|May 24, 2017
まとめ
研究者達は,ヒストンを正確に変化させるための合成触媒 (DSH) を開発し,遺伝子調節と病気に関する新しい洞察を可能にしました. この方法は,本来のクロマチンにおけるサイト固有のヒストンの翻訳後の改変 (PTM) を可能にします.
科学分野:
- エピジェネティクスと分子生物学
- クロマチン生物学
- 化学生物学
背景:
- ヒストンの翻訳後の改変 (PTM) は,遺伝子転写の調節に不可欠である.
- 制御不能のヒストンのPTMは癌のような病気と関連しています
- 現在の方法は,複雑なヒストンネットワーク内のPTMを研究するためのサイト選択性が欠けている.
研究 の 目的:
- ネイティブクロマチンのサイト選択的改変のための新しい方法を開発する.
- クロマチン構造と遺伝子調節における特定のヒストンPTMの機能的役割を調査する.
主な方法:
- DMAP-SH (DSH) という合成触媒は,生理学的条件下でチオエステルを活性化するために開発された.
- DSHは,標的型投与のために,核素結合体 (例えば,LANAペプチド) と結合された.
- DSHコンジュガートは,自然および非自然PTMをリコンビナントおよびネイティブクロマチンのヒストンに導入するために使用されました.
主要な成果:
- DSHは,特定のライシン残留物において,様々なPTM (アセチル化,マロニル化,ユビキチネーション,アジド-,およびフォスフォリルラベル) を成功裏に促進した.
- ヒストンH2Bライシン-120 (K120) のアサイレーションはLANA-DSHを用いて達成された.
- K120のアセチル化とマロニル化により,核細胞間相互作用を減少させることで,高級染色体の構造が調節された.
結論:
- DSH触媒は先天性クロマチンのサイト選択性ヒストンPTMを可能にし,以前の方法論的制限を克服しました.
- このアプローチは,個々のPTMとPTMネットワークにおけるその役割の研究を容易にする.
- この方法は,クロマチンの調節メカニズムを解剖し,疾患の病原性を理解するために多岐にわたる応用を提供します.
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