腫瘍抑制遺伝子p15をその反感覚RNAによってエピジェネティックサイレンシングする
Wenqiang Yu1, David Gius, Patrick Onyango
1Center for Epigenetics and Department of Medicine, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, Maryland 21205, USA.
Nature
|January 11, 2008
まとめ
自然なアンチセンセスのRNAは,がんにおけるp15のような腫瘍抑制遺伝子 (TSG) を沈黙させることができる. このプロセスは,ヘテロクロマチン形成とDNAメチル化を含み,腫瘍発生における遺伝子静止を誘発する可能性がある.
科学分野:
- 分子生物学は分子生物学である.
- エピジェネティクス エピジェネティクス
- 癌生物学 癌生物学について
背景:
- 腫瘍抑制遺伝子 (TSG) は,細胞の成長を抑制するために不可欠であり,がんではしばしば表遺伝的に静止されます.
- DNAメチル化はTSGサイレンシングの既知のメカニズムですが,非コーディングRNA,特にアンチセンセスのRNAの役割はますます認識されています.
- 反感覚RNAは,感覚RNAと相互作用し,遺伝子発現と表遺伝的変化に影響を与える.
研究 の 目的:
- 癌における腫瘍抑制遺伝子の表遺伝子静止における天然の反意味RNAの役割を調査する.
- 抗意味RNA,特にp15ASが白血病におけるp15遺伝子を静止させるメカニズムを解明する.
- アンチセンセスのRNAがヘテロクロマチン形成とDNAメチル化を開始し,TSGサイレンシングにつながるかどうかを判断する.
主な方法:
- 白血病のサンプルにおけるp15反感覚 (p15AS) とp15感覚表現の分析.
- cis および trans の p15AS 発現コンストクトの生成により, cis および trans の p15 サイレンシングに対するその効果を研究する.
- メチル化およびヘテロクロマチン阻害剤による治療により,p15AS誘発サイレンシングへの影響を評価する.
- マウスの胚性幹細胞における外因的なp15ASの発現は,p15の静止と細胞成長に対するその影響を評価するためである.
主要な成果:
- 白血病におけるp15ASとp15感覚表現の間の逆相関が観察されました.
- p15AS発現構造は,最初はDNAメチル化とは無関係に,ヘテロクロマチン形成によるp15サイレンシングを誘導した.
- 誘発された静音化は,p15AS発現が止まった後も持続していたが,阻害剤で逆行可能であった.
- マウスの胚性幹細胞における外因的なp15ASの発現は,p15の静止と成長の増加をもたらし,その後にDNAメチル化が差異化に伴いました.
結論:
- p15ASのような天然のアンチセンセスのRNAは,ヘテロクロマチン形成とDNAメチル化のためのトリガーとして機能することができます.
- Antisense RNA媒介によるTSGの静止は,腫瘍発生における重要なメカニズムである.
- この研究は,癌の発症における表遺伝的調節とTSG不活性化のための新しい経路を強調しています.
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