マルチスケール・フットプリントは,シス規制要素の組織を明らかにする
Yan Hu1,2, Max A Horlbeck1,2,3, Ruochi Zhang1,2,4
1Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Nature
|January 22, 2025
まとめ
我々は新しい計算手法であるPRINTを開発し,シス調節要素 (CREs) のDNAとタンパク質の相互作用を分析しました. このツールは,細胞の発達と老化中に CREs がどのように変化するかを明らかにし,遺伝子調節と病気の洞察を提供します.
科学分野:
- ゲノミクス
- コンピュータ生物学
- エピジェネティクス
背景:
- シス調節要素 (Cis-regulatory elements, CRE) は遺伝子発現に不可欠であるが,その動的タンパク質組織は十分に理解されていない.
- 既存の方法は,CREsにおけるエフェクタータンパク質組織の全ゲノム分析を制限し,細胞の運命と疾患に関する機能的研究を妨げています.
研究 の 目的:
- ゲノム全体でCREsのエフェクタータンパク質組織を測定するための計算方法を開発する.
- 転写因子と核細胞結合を推論し,CREsの規制論理を解釈する.
- 血液形成と老化中のCREの動態を調査する.
主な方法:
- クロマチンのアクセシビリティデータからDNAとタンパク質の相互作用の足跡を特定する計算方法であるPRINTを開発した.
- タンパク質結合の正確な推論のためのディープラーニングを使用してseq2PRINTフレームワークを作成しました.
- seq2PRINTをヒトの骨髄とネズミの造血幹細胞からの単細胞クロマチンアクセシビリティデータに適用した.
主要な成果:
- 観察されたCREsの連続的な確立と拡大は,ヒトの血液形成中に先駆的な因子に焦点を当てた.
- ネズミの造血幹細胞のCRE構造の年齢に関連した変化が発見され,核細胞の足跡が減少した.
- 老いたネズミの造血幹細胞で de novo Ets複合モチーフの増加を特定した.
結論:
- クロマチンのアクセシビリティデータからDNA結合タンパク質のダイナミクスについての洞察を得るために方法を確立しました.
- 差異化と老化過程における規制要素の構造を明らかにした.
- 細胞の運命と病気における規制要素の機能を理解するための枠組みを提供した.
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