ヒストンのH3K36変異は,変化したヒストンのメチル化経路を通じてサルコマゲネシスを促進する

Chao Lu¹, Siddhant U Jain², Dominik Hoelper²

¹Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA.

Science (New York, N.Y.)

|May 14, 2016

まとめ

ヒストンH3変異 (H3K36M) は細胞の分化を阻害し,メチル化パターンを破壊してサルコマの形成を促します. このメカニズムは小児がんやヒトの無差別性肉腫で観察されています.

科学分野:

分子生物学
癌生物学
エピジェネティクス

背景:

小児がんはしばしばヒストンH3の誤った変異を呈する.
これらのヒストンの変異によって引き起こされる腫瘍学的メカニズムは十分に理解されていません.

研究の目的:

メゼンキマの原始細胞における H3K36M 変異の機能的影響を調査する.
H3K36Mによる腫瘍形成の基礎となる分子メカニズムと,ヒトの肉腫に対するその関連性を解明する.

主な方法:

H3K36M変異モデルを用いた in vivo 研究
H3K36メチルトランスフェラーゼの活性を評価する酵素測定法
ヒストンメチル化パターン (H3K36me,H3K27me) とポリコンブ抑制複合体1 (PRC1) の分布の分析
人間の無差別サルコマのサンプルにおけるH3K36M/I変異の特定

主要な成果:

H3K36M変異はメゼンキマ原細胞の分化を阻害し,インビボでは未分化サルコマを誘発する.
H3K36M変異核細胞は,H3K36メチルトランスフェラーゼの枯渇またはH3K36I変異の効果を模倣して,H3K36メチルトランスフェラーゼを阻害する.
H3K36メチル化が失われると,H3K27メチル化が増加し,PRC1の再配分,分化阻害遺伝子の抑制が減少する.
新しいH3.1 K36M/ I変異がヒトの無差別サルコマで確認された.

結論:

H3K36Mの変異は,メゼンキマの微分化の表遺伝的調節を妨害することによって,サルコマの発症を誘導する.
ヒストンのメチル化とPRC1の活性が変化した新たな腫瘍発生メカニズムが明らかになった.
この研究は,ヒトの未分類性肉腫における潜在的な要因として,H3 K36M/ I変異を特定し,臨床前モデルとヒトの疾患を関連付けています.

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