Regulation of Liver-Specific Gene Expression

肝细胞核因子4(HNF4)是核受体超家族中高度保守的成员 配体依赖的转录因子。它是一种必不可少的基因，在早期发育中起着关键作用， 在成人的肝脏、肾脏、胰腺和肠道中也是如此。HNF4已经直接与几个 人类疾病，包括糖尿病和血友病，并与其他疾病间接相关，包括动脉粥样硬化 和癌症。HNF4是肝脏中含量最丰富的转录因子之一。而许多靶基因 已经被确认为HNF4，最近的基因组规模分析表明，还有更多的人尚未被发现 已确认身份。例如，最近的研究结果表明，人类的靶基因可能存在差异。 通过选择性剪接和启动子的使用产生不同的HNF4亚型。此外，HNF4是 已知是一种高度磷酸化的蛋白质，并对各种细胞内外信号做出反应； 然而，只有几个亚磷酸盐被绘制和充分表征。最后，除了它的 在中间代谢中的作用，越来越多的证据表明HNF4也可能在 在调节细胞周期中的作用。为了解决这些问题，我们提出了以下三个具体建议 目的：1)利用基因组规模分析和活体小鼠模型确定HNF4的新靶基因 研究HNF4亚型的功能差异；2)研究酪氨酸磷酸化在 HNF4的功能；3)研究HNF4在调节细胞周期中的作用。拟议中的实验 将继续研究HNF4在肝脏特异性基因表达中的作用 现代技术。这一结果将进一步加深我们对组织特异性基因机制的理解 监管。他们还将提供有关各种人类疾病的宝贵信息，这些疾病 与HNF4有关。最后，作为潜在的药物靶点，对靶向基因有了更全面的了解 通过HNF4，以及靶向HNF4的信号通路，将是发展适当的 治疗。

Hepatocyte nuclear factor 4 (HNF4) is a highly conserved member of the nuclear receptor (NR) superfamily of ligand-dependent transcription factors. It is an essential gene, playing a critical role in early development, as well as in the adult in the liver, kidney, pancreas and intestine. HNF4 has been directly linked to several human diseases including diabetes and hemophilia and indirectly linked to others including atherosclerosis and cancer. HNF4 is one of the most abundant transcription factors in the liver. Whereas many target genes have been identified for HNF4, recent genome-scale analyses indicate that there are many more yet to be identified. Recent results indicate, for example, that there may be differences in the target genes of the different isoforms of HNF4 generated by alternative splicing and promoter usage. Furthermore, HNF4 is known to be a heavily phosphorylated protein and to respond to a variety of intra- and extracellular signals; however, only a few of the phosphosites have been mapped and fully characterized. Finally, in addition to its role in intermediary metabolism, there is a growing body of evidence indicating that HNF4 may also play a role in regulating the cell cycle. In order to address these issues, we propose the following three Specific Aims: 1) Identify new target genes for HNF4 using genome-scale analysis and an in vivo mouse model to examine the functional differences in HNF4 isoforms; 2) Investigate the role of tyrosine phosphorylation in HNF4 function; and 3) Investigate the role of HNF4 in regulating the cell cycle. The proposed experiments will continue the investigation of the role of HNF4 in liver-specific gene expression using a broad array of modem techniques. The results will further our understanding of the mechanisms of tissue-specific gene regulation. They will also provide invaluable information regarding a variety of human diseases that are linked to HNF4. Finally, as a potential drug target, a more comprehensive knowledge of the genes targeted by HNF4, as well as the signaling pathways that target HNF4, will be essential to developing appropriate therapies.