HDAC3のダイコトミックな活性が炎症反応を制御する
Hoang C B Nguyen1,2, Marine Adlanmerini1,2, Amy K Hauck1,2
1Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Nature
|August 8, 2020
まとめ
ヒストン脱酸化酵素3 (HDAC3) は遺伝子調節において二重の役割を果たします. 触媒活動から独立して転写活性化剤として作用し,先天的な免疫に不可欠な抑制剤である.
科学分野:
- 免疫学
- 分子生物学
- エピジェネティクス
背景:
- ヒストン脱エチラゼ (HDACs) は,遺伝子転写を調節する重要な染色体修正剤である.
- HDAC3は,その触媒活性のために核受容体核圧縮器 (NCoR1/2) を唯一必要とする.
- 全局的なHDAC3喪失が転写を抑制するメカニズムは不明である.
研究 の 目的:
- マクロファージの活性化におけるHDAC3の非正規的機能を明らかにする.
- 転写活性化剤と抑制剤としてのHDAC3の二分作用を調査する.
- 生まれながらの免疫におけるHDAC3の触媒作用を決定する.
主な方法:
- リポポリサッカライドを用いたマクロファージの活性化
- HDAC3結合部位を特定するためのクロマチンの免疫流出.
- 野生型とHDAC3欠乏したマウスの遺伝子発現の変化の分析.
- リポポリサッカライド試験後のマウスの生存率の評価
主要な成果:
- HDAC3は,マクロファージの活性化中にNCoR1/ 2とは独立して転写因子2 (ATF2) に結合した部位を活性化させ,非正規的なメカニズムで炎症遺伝子を活性化します.
- HDAC3sはATF3結合部位で活性化され,Toll型受容体のシグナリングを抑制する.
- HDAC3の損失は,その触媒的活動に関係なく,致命的なリポポリサッカリドの暴露からマウスを保護します.
結論:
- HDAC3は二分性の転写調節体として機能し,活性化剤と抑制剤の両方として作用する.
- HDAC3は,先天的な免疫反応に不可欠な,デセチラゼ独立機能を有する.
- HDAC3の非正規的機能をターゲットにすることで,炎症性疾患の治療戦略を提供することができる.
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