保护的NPPB+边界区域从MEF2-转换为AP-1-驱动的基因程序
Karel van Duijvenboden1, Dennis E M de Bakker2, Joyce C K Man1
1Departments of Medical Biology, Amsterdam Cardiovascular Sciences (K.v.D., J.C.K.M., R.J., M.G., I.B.H., P.B., V.M.C.), Academic Medical Center, Amsterdam, The Netherlands.
在心脏病发作附近存活的心脏细胞激活压力程序,包括B型尿素 (Nppb) 表达,这对于预防心力衰竭至关重要. 这种反应在人类中是保留的.
科学领域:
- 心脏病学
- 分子生物学
- 基因组学
背景情况:
- 心脏病发作后的边界区域包含具有独特微环境波动的存活心肌细胞.
- 这些边界心肌细胞在心脏再生中的作用越来越被认可.
研究的目的:
- 确定边界区域心肌细胞的独特转录和调节特性.
- 在心脏病发作后的边界区域识别和验证新的分子标志物.
主要方法:
- 使用转基因报告小鼠识别心肌梗塞后的Nppb阳性边界区域.
- 在偏远,边缘和心脏病发作区域进行RNA测序,并净化心肌细胞核.
- 在缺血性人心中验证了候选基因,并通过ATAC测序评估了染色质的可访问性.
主要成果:
- 确定了一个具有强烈应激反应的转录区,包括氧化酸化和脂肪酸代谢的下调.
- 在人类心脏中发现了保存的边界区域标记,包括NPPB,ANKRD1,DES,UCHL1,JUN和FOXP1.
- 证明Nppb缺乏的小鼠在心脏病发作后会出现致命的心力衰竭, 这突显了Nppb的关键作用.
结论:
- 边界区域心肌细胞从平稳的MEF2驱动程序转变为AP-1驱动的受伤诱导程序.
- 这种保存的转录开关包括Nppb表达,这对于预防急性心脏衰竭至关重要.
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