フォークヘッド ボックス プロテイン O1 の ゲノム 結合 パターン は,心臓 肥大 化 で その 独特 な 役割 を 明らか に し て い ます
Jessica Pfleger1, Ryan C Coleman1, Jessica Ibetti1
1Center for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA.
Circulation
|July 10, 2020
まとめ
フォークヘッドボックスタンパク質O1 (FoxO1) は,遺伝子発現とRNAポリメラーゼIIのダイナミクスを調節することによって,心臓の過剰成長を促進します. FOXO1を標的とした治療は,心筋縮の治療策を提供することができる.
科学分野:
- 心血管生物学
- 分子生物学
- 遺伝子規制
背景:
- 重要な遺伝子発現の変化と心筋細胞の大きさの増加を伴う.
- 新規募集と転写延長を含むRNAポリメラーゼII (pol II) の活動は,これらの変化の根底にある.
- フォークヘッドボックスタンパク質O1 (FoxO1) のような転写因子の役割は,心筋縮中にこれらのpol IIプロセスを分化的に調節する事は,ほとんど不明である.
研究 の 目的:
- 心臓の過剰成長中の遺伝子発現とポルIIダイナミクスの調節におけるFoxO1の役割を調査する.
- 心臓におけるFoxO1の遺伝子調節の範囲を研究する.
主な方法:
- FoxO1染色体免疫沈殿深層シーケンシング (ChIP-seq) は,イソプロテレノール注射または横動脈収縮を受けたマウスの心臓で実施された.
- FoxO1 ChIP-seqデータは,pol II ChIP-seqデータと統合され,pol IIの募集と延長に関連したFoxO1結合を分析した.
- FoxO1の機能は,心筋細胞高縮の文脈で,ノックダウンまたは消去戦略を使用してin vitroおよびin vivoで評価されました.
主要な成果:
- FOXO1のクロマチンの結合は,心筋縮時に増加し,その程度と正の相関関係にある.
- FoxO1は心臓発現遺伝子のプロモーターに結合し,横動脈収縮後に結合が増加する.
- フォックスO1結合は,ポルIIデノボ募集,損失,および一時放出によって調節される遺伝子で上昇し,後者において重要な役割を果たした.
- FoxO1のノックダウン/消去は,心筋細胞の過剰成長を防止し,重要な誘導性遺伝子の発現を減少させた.
結論:
- FoxO1は,ポルIIの新規募集と一時放出を調節することによって,心臓の過剰成長を媒介する.
- FoxO1-bound,pol II-regulated遺伝子のほとんどは,プレッシャーオーバーロード後にpol IIのパウズリリースを含む.
- これらの発見は,心筋縮におけるFoxO1の広範な転写的調節作用を強調し,治療目標としての可能性を示唆しています.
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