HDAC3活动的二元参与控制着炎症反应
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
概括
在基因调节中发挥双重作用. 它作为一个独立于其催化活性的转录激活剂和抑制剂,对先天免疫至关重要.
科学领域:
- 免疫学
- 分子生物学
- 表观遗传学
背景情况:
- 基因脱乙酶 (HDAC) 是调节基因转录的关键染色体修饰剂.
- HDAC3 独特地需要核受体核心压缩剂 (NCoR1/2) 进行催化活动.
- 全球HDAC3损失抑制转录的机制尚不清楚.
研究的目的:
- 阐明HDAC3在巨激活中的非正规功能.
- 研究HDAC3作为转录激活剂和抑制剂的二分作用.
- 确定HDAC3在先天免疫中的催化作用.
主要方法:
- 使用脂聚糖激活巨细胞.
- 染色体免疫沉以确定HDAC3结合的部位.
- 野生类型和HDAC3缺乏的小鼠的基因表达变化的分析.
- 在脂聚糖试验后评估小鼠的存活率.
主要成果:
- 在巨激活过程中,HDAC3被招募到独立于NCoR1/ 2的转录因子2 (ATF2) 结合位点上,通过非正规机制激活炎症基因.
- 在ATF3结合的部位中,HDAC3的脱乙酶活性会抑制Toll类受体信号传递.
- 无论其催化活性如何,HDAC3的损失都会保护小鼠免受致命的脂多糖暴露.
结论:
- HDAC3作为二分体的转录调节剂,同时作为激活剂和抑制剂.
- 在先天免疫反应中,HDAC3具有关键的脱乙酶独立功能.
- 针对HDAC3的非正规功能可能为炎症疾病提供治疗策略.
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