Professor and Chair, Department of Regenerative Medicine and Advanced Cardiac Therapeutics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, Japan.
Circ Res. 2010 Apr 2;106(6):1083-91. doi: 10.1161/CIRCRESAHA.109.214130. Epub 2010 Feb 18.
The transcriptional networks guiding heart development remain poorly understood, despite the identification of several essential cardiac transcription factors.
To isolate novel cardiac transcription factors, we performed gene chip analysis and found that Zac1, a zinc finger-type transcription factor, was strongly expressed in the developing heart. This study was designed to investigate the molecular and functional role of Zac1 as a cardiac transcription factor.
Zac1 was strongly expressed in the heart from cardiac crescent stages and in the looping heart showed a chamber-restricted pattern. Zac1 stimulated luciferase reporter constructs driven by ANF, BNP, or alphaMHC promoters. Strong functional synergy was seen between Zac1 and Nkx2-5 on the ANF promoter, which carries adjacent Zac1 and Nkx2-5 DNA-binding sites. Zac1 directly associated with the ANF promoter in vitro and in vivo, and Zac1 and Nkx2-5 physically associated through zinc fingers 5 and 6 in Zac1, and the homeodomain in Nkx2-5. Zac1 is a maternally imprinted gene and is the first such gene found to be involved in heart development. Homozygous and paternally derived heterozygous mice carrying an interruption in the Zac1 locus showed decreased levels of chamber and myofilament genes, increased apoptotic cells, partially penetrant lethality and morphological defects including atrial and ventricular septal defects, and thin ventricular walls.
Zac1 plays an essential role in the cardiac gene regulatory network. Our data provide a potential mechanistic link between Zac1 in cardiogenesis and congenital heart disease manifestations associated with genetic or epigenetic defects in an imprinted gene network.
尽管已经鉴定出了几个心脏转录因子，但指导心脏发育的转录网络仍知之甚少。
为了分离新的心脏转录因子，我们进行了基因芯片分析，发现锌指型转录因子 Zac1 在发育中的心脏中强烈表达。本研究旨在研究 Zac1 作为心脏转录因子的分子和功能作用。
Zac1 在心脏嵴阶段和心脏环化阶段强烈表达，表现出房室限制模式。Zac1 刺激由 ANF、BNP 或 alphaMHC 启动子驱动的荧光素酶报告基因构建体。Zac1 和 Nkx2-5 在 ANF 启动子上具有强烈的功能协同作用，该启动子携带相邻的 Zac1 和 Nkx2-5 DNA 结合位点。Zac1 可在体外和体内直接与 ANF 启动子结合，Zac1 和 Nkx2-5 通过 Zac1 中的锌指 5 和 6 以及 Nkx2-5 中的同源域物理结合。Zac1 是一个母系印迹基因，是第一个被发现参与心脏发育的印迹基因。携带 Zac1 基因座中断的纯合子和父系杂合子小鼠表现出腔室和肌丝基因水平降低、凋亡细胞增加、部分穿透性致死和形态缺陷，包括心房和室间隔缺损以及心室壁变薄。
Zac1 在心脏基因调控网络中发挥着重要作用。我们的数据为 Zac1 在心脏发生中的作用与印迹基因网络中遗传或表观遗传缺陷相关的先天性心脏病表现之间提供了潜在的机制联系。
