一个转录开关控制心脏病中的纤维细胞激活
Michael Alexanian1, Pawel F Przytycki1, Rudi Micheletti2
1Gladstone Institutes, San Francisco, CA, USA.
Nature
|June 24, 2021
概括
在心脏病中,主体和端外域 (BET) 抑制可逆控制纤维细胞激活. 这表明MEOX1是关键的调节剂,为纤维化疾病提供了新的治疗点.
科学领域:
- 心血管生物学
- 表观遗传学
- 纤维化研究
背景情况:
- 疾病器官的压力信号会引发不适应性细胞状态转变,包括纤维细胞激活,恶化器官损伤.
- 纤维细胞激活是肺部,肝脏,脏和心脏疾病中常见但不太了解的应激反应.
- 在缓解心脏功能障碍方面,odomain和额外终端域 (BET) 蛋白抑制具有前景.
研究的目的:
- 通过单细胞表观学来研究纤维细胞激活的机制基础.
- 在心脏细胞中识别由BET抑制剂调节的可逆转录开关.
- 发现纤维化疾病的新疗法.
主要方法:
- 用BET抑制剂治疗的心脏的单细胞表观基因分析.
- 用于识别动态DNA元素的染色体可访问性分析.
- 抑制CRISPR以评估特定的cis元素和转录因子的作用
主要成果:
- 抑制BET诱导了一个可逆的转录开关,控制心脏中的纤维细胞激活.
- 确定与心脏表现相关的动态DNA元素.
- 发现MEOX1是纤维细胞激活的关键调节者,对于TGFβ诱导的激活至关重要,并且与纤维细胞基因程序相关.
结论:
- MEOX1是心脏功能障碍中纤维细胞激活的中心调节者.
- 在纤维细胞中依赖BET调节MEOX1提供了潜在的治疗策略.
- 人类肺部,肝脏和脏纤维细胞中MEOX1的升级表明它在治疗纤维性疾病方面具有广泛的适用性.
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