DNAメチル化と転写因子の競争がNRF1の結合を決定する

Silvia Domcke^1,2, Anaïs Flore Bardet¹, Paul Adrian Ginno¹

¹Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH 4058 Basel, Switzerland.

Nature

|December 18, 2015

まとめ

DNAメチル化は,特にNRF1の転写因子 (TF) の結合を制限する. TF結合は低メチル化を促進し,さらなるTF占有と遺伝子調節を可能にします.

科学分野:

エピジェネティクスと遺伝子調節
分子生物学
ゲノミクス

背景:

ユカリオット転写因子 (TF) は遺伝子活動を制御するが,そのDNAモチーフのサブセットにのみ結合する.
クロマチンの構造はTFのアクセシビリティを制限する可能性があるが,TF結合を誘導するクロマチンの状態の役割は不明である.
DNAメチル化はゲノム機能に影響を与える重要なエピジェネティックマークです

研究の目的:

制限された転写因子結合に対するDNAメチル化の貢献を調査する.
クロマチンの状態,特にDNAメチル化が,幹細胞におけるTF結合をどのように指示するかを理解する.

主な方法:

DNAメチル化と非メチル化条件下でマウンの幹細胞におけるDNase-I過敏部位のマッピング.
メチル化制限地域におけるTFモチーフ濃縮の分析
DNAメチル化変化とTF相互作用に対するNRF1結合ダイナミクスの評価

主要な成果:

メチル化が制限されている部位は,CpGを含むTFモチーフ,特にNRF1のために濃縮されます.
転写因子NRF1は,非メチル化ゲノムの数千の追加部位に結合し,転写を増加させます.
DNAメチルトランスフェラーゼの活性が回復すると,NRF1結合を上回るリメチル化が起こります.
隣接するモチーフまたはTFの除去は,局所的なハイパーメチル化とNRF1結合の喪失を引き起こし,DNAメチル化によるTF協力性を示す.

結論:

特にNRF1のようなメチル化に敏感なTFには,TF結合への障壁として作用する.
DNAメチル化に敏感なTFの結合には,局所的な低メチル化を誘導する追加の決定因子が必要になる可能性があります.
いくつかの因子によるメチル化除去が他の因子による占有を可能にする場合,規制領域の低メチル化を説明する協力性の原則が存在する.

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