Trans-acting Factors Causing Cell Specific Gene Control

引起细胞特异性基因控制的反式作用因子

基本信息

批准号：
8448283
负责人：
Kenneth Zaret
金额：
$ 52.68万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
1986
资助国家：
美国
起止时间：
1986-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8448283
关键词：
Architecture Biological Models Cell Nucleus Cell Separation Cells Chromatin Competence Development Diagnostic Disease Embryo Enabling Factors Endoderm Endoderm Cell Foxes Functional disorder Gene Targeting Genes Genetic Genetic Programming Genome Genome Scan Genomics Goals Grant Hepatic Hepatocyte Hormone Responsive Instruction Laboratories Life Liver Malignant Neoplasms Mammalian Cell Molecular Molecular Biology Multipotent Stem Cells Mus Preclinical Drug Evaluation Primitive foregut structure Proteins Research Research Personnel Signal Pathway Signal Transduction Stem cells Technology Therapeutic Trans-Activators Transgenes Translating Work adult stem cell base cancer cell cell type chromatin immunoprecipitation embryonic stem cell extracellular human disease insight pluripotency progenitor programs response transcription factor

项目摘要

The long-term goal of this grant is to reveal molecular mechanisms by which particular cell type choices are made in multipotent progenitor cells in the mammalian embryo. The research seeks to understand how extracellular signals converge on progenitor cells to induce a cell fate choice and how multipotent progenitors gain the competence to choose certain fates and be excluded from others. Since the vast majority of embryonic progenitors, adult stem cells, and perhaps cancer progenitors in the body are multipotent, not pluripotent, understanding the principles by which multipotent progenitors gain their special competencies and limitations is of fundamental biomedical importance. As a model system, we investigate the specification of liver progenitors from multipotent foregut endoderm cells in the early mouse embryo. These studies identified the concept that pioneer transcription factors help establish cell type competency by opening up local domains of chromatin at silent liver target genes in the endoderm. We hypothesize that transcription factors that convert differentiated cells to pluripotency can function as pioneer factors. Recently, we discovered co-regulators that modify chromatin architecture with FoxA pioneer factors and revealed the basis by which Fox proteins, compared to other factors, scan the genome in the living cell nucleus. In addition, we discovered a dynamic signaling network that induces the hepatic fate In multipotent endoderm, and more recently have traced the inducing signals down to the chromatin of recipient target genes. Our integrative view is enabled by our development of new cell sorting capacities from early embryos and scaled-down molecular biology and chromatin immunoprecipitation technology. Finally, we can now trace the fate and function of different types of progenitor cells in the mammalian foregut. We performed genomic expression analysis of different patches of endoderm cells and then made cre-ER transgenes driven by the differentially expressed genes. Our basic findings have been translated by many other laboratories to explain how pioneer factors enable cancer cells to be hormone responsive and to differentiate embryonic stem cells into endoderm cells and liver cells. Further work from this grant is anticipated to provide insights into the mechanisms of cell programming and the means by which different progenitor types can be programmed to particular ceil fates.

该赠款的长期目标是揭示特定细胞类型的分子机制在哺乳动物胚胎中的多能祖细胞中做出选择。研究试图了解细胞外信号如何在祖细胞上融合以诱导细胞命运选择以及如何多能祖先获得了选择某些命运并将其排除在其他命运之外的能力。自从绝大多数胚胎祖细胞，成年干细胞以及体内癌症祖细胞是多能理解多能祖细胞获得特殊的原理能力和局限性具有基本的生物医学重要性。作为模型系统，我们调查早期小鼠胚胎中多能腹膜内胚层细胞的肝脏祖细胞的规范。这些研究确定了先锋转录因子有助于通过在内胚层中，在沉默的肝靶基因上打开染色质的局部结构域。我们假设这一点将分化细胞转换为多能性的转录因子可以用作先锋因素。最近，我们发现了与FoxA先驱因素和FOXA先锋因素和揭示了与其他因素相比，FOX蛋白在活细胞中扫描基因组的基础核。此外，我们发现了一个动态信号网络，该网络诱导了肝脏命运内胚层以及最近将诱导信号追溯到接受者目标的染色质基因。我们的综合观点可以通过我们从早期胚胎中开发新的细胞分类能力来启用我们的观点以及缩放的分子生物学和染色质免疫沉淀技术。最后，我们现在可以追踪哺乳动物前肠中不同类型的祖细胞的命运和功能。我们表演了内胚层细胞的不同斑块的基因组表达分析，然后进行CRE-ER转基因由差异表达的基因驱动。我们的基本发现已被许多其他人翻译实验室解释了开拓性因素如何使癌细胞能够反应激素并分化胚胎干细胞进入内胚细胞和肝细胞。预计这笔赠款的进一步工作将提供有关细胞编程机制以及不同祖细胞类型的手段的见解可以编程为特定的CEIL命运。