Regulation of Liver-Specific Gene Expression

项目摘要 肝细胞核因子4(HNF4)是核内高度保守的成员。 受体(NR)超家族的配体依赖的转录因子。这是一个 必需基因，在早期发育中起关键作用，在成人中也是如此 在肝脏、肾脏、胰腺和肠道。HNF4已直接与 包括糖尿病和血友病在内的几种人类疾病与 对其他疾病，包括动脉粥样硬化和癌症。HNF4是最多的 肝脏中有丰富的转录因子。而许多靶基因都有 被确认为HNF4，最近的基因组规模分析表明有 还有更多的人有待确认。例如，最近的结果表明， 可能是HNF4不同亚型靶基因的差异 由选择性剪接和启动子使用产生。此外，HNF4是 已知是一种高度磷酸化的蛋白质，并对多种内源蛋白做出反应 和细胞外信号；然而，只有少数亚磷酸盐被 绘制了地图并充分刻画了特征。最后，除了它在中介中的作用 新陈代谢方面，越来越多的证据表明，HNF4也可能 在调节细胞周期方面发挥作用。为了解决这些问题，我们 提出以下三个具体目标：1)发现新的HNF4靶基因 使用基因组规模的分析和活体小鼠模型来检查 HNF4亚型的功能差异；2)研究酪氨酸的作用 HNF4功能中的磷酸化；以及3)研究HNF4在 调节细胞周期。拟议中的实验将继续 用一种广谱方法研究HNF4在肝脏特异性基因表达中的作用 一系列现代技术。研究结果将进一步加深我们对 组织特异性基因调控的机制。它们还将提供无价的 关于与HNF4有关的各种人类疾病的信息。 最后，作为潜在的药物靶点，更全面地了解 HNF4靶向的基因以及靶向HNF4的信号通路将 对于开发适当的治疗方法至关重要。项目叙事 我们的研究与公共健康相关，因为它试图破译 肝脏和肠道中基因被启动的机制。这一点很重要 仅仅是为了了解糖尿病、肥胖症、 动脉粥样硬化和癌症，而且还设计了治疗这些疾病的新疗法 疾病。

Project Summary 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 modern 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. Project Narrative Our research is relevant to public health because it attempts to decipher the mechanisms by which genes are turned on in the liver and gut. This is critical not only for understanding the causes of diseases such as diabetes, obesity, atherosclerosis and cancer, but also for designing new therapies to treat those diseases.