隔離器の機能不全とIDH変異性グリオマにおける腫瘍遺伝子の活性化

William A Flavahan^1,2,3, Yotam Drier^1,2,3, Brian B Liau^1,2,3

¹Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.

Nature

|December 25, 2015

まとめ

IDH変異は,DNAメチル化とCTCF結合を妨害し,異常な遺伝子活性化につながり,腫瘍の成長を促します. このエピジェネティック障害は染色体のトポロジーと腫瘍遺伝子の発現に影響します.

科学分野:

腫瘍学
エピジェネティクス
分子生物学

背景:

アイソチラート脱水素酵素 (IDH) の機能獲得変異は,主要な膠原腫サブクラスを定義する.
変異したIDHは,DNA脱メチル化に関与するTETヒドロキシラーゼを阻害して,2-ヒドロキシグルタレットを産生する.
IDH変異性膠原腫はCpG島メチレーターフェノタイプ (G-CIMP) を表しているが,その機能的役割は不明である.

研究の目的:

IDH変異性膠原腫における変化したDNAメチル化の機能的影響を調査する.
CCCTC結合因子 (CTCF) がIDH変異性グリオマゲネシスにおける役割を決定する.
IDH 変異が異常遺伝子発現とグリオマ発症を促進するメカニズムを解明する.

主な方法:

ヒトのIDH変異性グリオマにおけるコヘシンとCTCF結合部位におけるDNAメチル化パターンの分析
CTCF結合,DNAメチル化,およびIDH変異体および野生型膠質球における遺伝子発現の評価.
CRISPR-Cas9技術を活用して,IDHの野生型膠質球のCTCFモチーフを破壊した.

主要な成果:

IDH変異性グリオマは,CTCF結合部位でハイパーメチル化を示し,CTCF結合を減少させ,トポロジカルドメインの隔離を破壊する.
ドメインの境界でのCTCF結合の喪失は,PDGFRA腫瘍遺伝子との異常な強化剤の相互作用を可能にします.
脱メチル化剤は,IDH変異のグリモスフィアの断熱機能を部分的に回復し,PDGFRAをダウンレギュレーションした.
IDHワイルド型グリオマスフィアのCTCFモチーフの破壊はPDGFRAを上昇させ,増殖を促した.

結論:

IDH変異は,表遺伝的変異を通じて染色体トポロジーを破壊することによって,グリオマゲネシスを促進する.
CTCF分離器の機能の障害は,特にPDGFRA腫瘍遺伝子の異常な活性化につながる.
エピジェネティック・ディスレギュレーションを標的とした治療は,IDH変異性グリオマの潜在的治療戦略です.

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