表观遗传阅读器BRD4 (含基蛋白4) 控制核编码的线粒体转录组以调节心脏功能
Soo Young Kim1, Xin Zhang2, Gabriele G Schiattarella1
1Division of Cardiology, Department of Internal Medicine (S.Y.K., G.G.S., F.A., K.M.F., N.J., P.A.S., H.I.M., X.L., L.I.S., S.L., T.G.G., J.A.H.), University of Texas Southwestern, Dallas.
Circulation
|October 28, 2020
概括
对于维持正常的心脏功能来说,BRD4蛋白质是必不可少的. 心肌细胞中的BRD4损失导致扩大心肌病并破坏线粒体的能量产生,突出显示了它在心脏健康中的关键作用.
科学领域:
- 心血管生物学
- 表观遗传学
- 线粒体生理学
背景情况:
- 包括BRD4在内的BET蛋白是癌症和心血管疾病的治疗点.
- 药物抑制剂如JQ1在临床前的心力衰竭模型中表现有前途.
- 对BRD4在心脏中的作用缺乏遗传验证.
研究的目的:
- 通过遗传方法研究BRD4在心脏病理学中的功能.
- 阐明BRD4在心脏发育和成熟功能中的作用.
- 验证BET抑制剂药理学研究的结果.
主要方法:
- 产生了心肌细胞特异性的BRD4淘汰小鼠模型.
- 进行了全面的功能,转录和线粒体分析.
- 使用计算分析来识别调节性转录因素.
主要成果:
- BRD4 损失导致心脏功能逐渐下降,导致扩大心肌病.
- 转录组分析显示了线粒体能量生产基因的破坏.
- 线粒体研究证实了变化的电子运输链活动.
- 与雌激素相关的受体α被确定为BRD4依赖基因的关键调节者.
结论:
- 在心肌细胞线粒体平衡中,BRD4起着至关重要的,以前未知的作用.
- 对于维持正常的心脏功能来说,BRD4是不可或缺的.
- 与药物抑制相比,BRD4的遗传切除具有明显而严重的后果.
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