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首页> 外文期刊>Molecular and Cellular Biology >Threshold Levels of Hepatocyte Nuclear Factor 6 (HNF-6) Acting in Synergy with HNF-4 and PGC-1α Are Required for Time-Specific Gene Expression during Liver Development
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Threshold Levels of Hepatocyte Nuclear Factor 6 (HNF-6) Acting in Synergy with HNF-4 and PGC-1α Are Required for Time-Specific Gene Expression during Liver Development

机译：肝发育过程中特定时间的基因表达需要与HNF-4和PGC-1α协同作用的肝细胞核因子6（HNF-6）阈值水平

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During liver development, hepatocytes undergo a maturation process that leads to the fully differentiated state. This relies at least in part on the coordinated action of liver-enriched transcription factors (LETFs), but little is known about the dynamics of this coordination. In this context we investigate here the role of the LETF hepatocyte nuclear factor 6 (HNF-6; also called Onecut-1) during hepatocyte differentiation. We show that HNF-6 knockout mouse fetuses have delayed expression of glucose-6-phosphatase (g6pc), which catalyzes the final step of gluconeogenesis and is a late marker of hepatocyte maturation. Using a combination of in vivo and in vitro gain- and loss-of-function approaches, we demonstrate that HNF-6 stimulates endogenous g6pc gene expression directly via a synergistic and interdependent action with HNF-4 and that it involves coordinate recruitment of the coactivator PGC-1α. The expression of HNF-6, HNF-4, and PGC-1α rises steadily during liver development and precedes that of g6pc. We provide evidence that threshold levels of HNF-6 are required to allow synergism between HNF-6, HNF-4, and PGC-1α to induce time-specific expression of g6pc. Our observations on the regulation of g6pc by HNF-6 provide a model whereby synergism, interdependency, and threshold concentrations of LETFs and coactivators determine time-specific expression of genes during liver development.
机译：在肝脏发育过程中，肝细胞会经历成熟过程，从而进入完全分化状态。这至少部分取决于肝脏富集的转录因子（LETF）的协同作用，但对这种协调的动力学了解甚少。在这种情况下，我们在这里研究LETF肝细胞核因子6（HNF-6;也称为Onecut-1）在肝细胞分化过程中的作用。我们显示HNF-6基因敲除小鼠胎儿已延迟了葡萄糖-6-磷酸酶（ g6pc ）的表达，这催化了糖异生的最后一步，是肝细胞成熟的晚期标志物。结合使用体内和体外功能获得和丧失功能的方法，我们证明了HNF-6通过与HNF-4的协同和相互依赖的作用直接刺激内源性 g6pc 基因表达，并且它涉及协同活化PGC-1α的募集。 HNF-6，HNF-4和PGC-1α的表达在肝脏发育过程中稳定上升，并且先于 g6pc 。我们提供的证据表明，需要HNF-6的阈值水平才能使HNF-6，HNF-4和PGC-1α之间的协同作用诱导 g6pc 的时间特异性表达。我们对HNF-6对 g6pc 的调节的观察提供了一个模型，在该模型中，LETFs和共激活因子的协同作用，相互依赖性以及阈值浓度决定了肝脏发育过程中基因的时间特异性表达。

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