Genome-wide orchestration of cardiac functions by the orphan nuclear receptors ERRα and γ
Genome-wide orchestration of cardiac functions by the orphan nuclear receptors ERRα and γ
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DOI：
10.1016/j.cmet.2007.03.007
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发表时间：
2007-05-01
期刊：
影响因子：
29
通讯作者：
Giguere, Vincent
中科院分区：
文献类型：
--
作者：
Dufour, Catherine R.;Wilson, Brian J.;Giguere, Vincent
孤儿核受体雌激素相关受体α（NR3B1）被认为是线粒体生物发生的关键调节因子，但尚不清楚雌激素相关受体α及其他异构体是否在心脏能量学和功能中发挥更广泛的作用。我们利用全基因组定位分析和表达谱分析来评估雌激素相关受体α和γ（NR3B3）在成年心脏中的作用。我们的数据表明，这两种受体作为非必需的异二聚体，作用于一组共同的启动子，这些启动子涉及能量底物的摄取、ATP在线粒体膜上的产生和运输、细胞内燃料感知以及钙离子处理和收缩活动。通过功能研究辅助的基序发现算法表明，雌激素相关受体作用的启动子富含核呼吸因子 - 1（NRF - 1）、环磷腺苷效应元件结合蛋白（CREB）和信号转导及转录激活因子3（STAT3）结合位点。因此，我们的研究揭示雌激素相关受体协调一个全面的心脏转录程序，并进一步表明调节雌激素相关受体的活性可用于治疗心肌病。
Orphan nuclear receptor ERR alpha (NR3B1) is recognized as a key regulator of mitochondrial biogenesis, but it is not known whether ERR alpha and other ERR isoforms play a broader role in cardiac energetics and function. We used genome-wide location analysis and expression profiling to appraise the role of ERR alpha and gamma (NR3B3) in the adult heart. Our data indicate that the two receptors, acting as nonobligatory heterodimers, target a common set of promoters involved in the uptake of energy substrates, production and transport of ATP across the mitochondrial membranes, and intracellular fuel sensing, as well as Ca2+ handling and contractile work. Motif-finding algorithms assisted by functional studies indicated that ERR target promoters are enriched for NRF-1, CREB, and STAT3 binding sites. Our study thus reveals that the ERRs orchestrate a comprehensive cardiac transcriptional program and further suggests that modulation of ERR activities could be used to manage cardiomyopathies.