DNMT3Aの自己抑制とヒストンH3誘発活性化に関する構造的洞察

Xue Guo¹, Ling Wang¹, Jie Li²

¹1] Fudan University Shanghai Cancer Center, Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China [2] State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China.

Nature

|November 11, 2014

まとめ

DNAメチルトランスフェラーゼ3A (DNMT3A) は,自身の構造によって抑制されるが,ヒストンH3尾によって活性化される. このヒストンの相互作用は自己抑制を解放し,特定のゲノム部位でのDNAメチル化を可能にします.

科学分野:

エピジェネティクスと分子生物学
構造生物学構造生物学とは
バイオケミストリーバイオケミストリー

背景:

DNAメチル化は,遺伝子発現,インプリント,遺伝を調節する重要なエピジェネティック変異です.
De novo DNAメチルトランスフェラーゼ,DNMT3AとDNMT3Bは,哺乳類の胚形成中にメチル化パターンを確立する.
関連するタンパク質であるDNMT3LはDNMT3Aの活性を増強し,ヒストンの改変がDNAメチル化の確立を導く.

研究の目的:

ヒストンH3がDNMT3Aの活性を刺激する分子メカニズムを解明する.
DNMT3Aの自己抑制メカニズムとその調節を調査する.
ヒストンH3によるDNMT3A活性化の構造的基礎を決定する.

主な方法:

DNMT3A-DNMT3L (自己抑制) とDNMT3A-DNMT3L-H3 (活性) 複合体の結晶構造の決定.
酵素活性とDNA結合を分析するための生化学分析.
DNMT3AドメインとヒストンH3.3の相互作用の構造分析

主要な成果:

DNMT3Aは,ATRX-DNMT3-DNMT3L (ADD) ドメインが,DNA結合を阻害することによって,触媒ドメイン (CD) を阻害する自己抑制形状に存在する.
ヒストンH3 (特にH3K4me3ではない) はADD-CD相互作用を妨害し,自己抑制を解放し,DNMT3Lと独立してDNMT3Aを活性化します.
構造データは,ヒストンH3結合時にADDドメインの大きな構成変化を明らかにし,DNMT3Aの活性化につながります.

結論:

ヒストンH3結合は,DNAメチル化のための規制層を提供し,メチル化されていないH3K4で適切な場所での酵素活性化を保証します.
この発見は,H3K4me3と哺乳類のゲノム全体におけるDNAメチル化との間の負の相関を裏付けている.
この研究は,ヒストンH3によって緩和されるDNMT3Aの予期せぬ自己抑制メカニズムを明らかにし,表遺伝学的調節に関する新しい洞察を提供します.

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