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Temporal, cell type- and locus-specific epigenetic control in transgenic mice

转基因小鼠的时间、细胞类型和位点特异性表观遗传控制

基本信息

批准号：
8642528
负责人：
Linda Madisen
金额：
$ 46.36万
依托单位：
ALLEN INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-30 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8642528
关键词：
Adult Alleles Animals Binding Biological Assay Biological Models Biology Brain Brain Diseases Cell Maintenance Cell physiology Cells Cellular Morphology Development Disease Doxycycline EP300 gene ES Cell Line Ensure Epigenetic Process Future Gene Expression Gene Expression Regulation Generations Genes Genetic Genome HDAC1 gene Histocompatibility Testing In Vitro Knock-in Mouse Label Life Malignant Neoplasms Mediating Mental disorders Methodology Modeling Modification Molecular Mus Neocortex Neurons Organ Organism Phenotype Proteins Reporter Response Elements Specificity Technology Testing Tetracyclines Time Tissues Trans-Activators Transcription Coactivator Transgenes Transgenic Mice Transgenic Organisms Validation Withdrawal Work base cell type design design and construction embryo cell embryonic stem cell human ZNF45 protein in vivo insight interest knock-down mouse genome nerve stem cell overexpression prevent progenitor public health relevance recombinase small hairpin RNA tissue culture tool transgene expression

项目摘要

DESCRIPTION (provided by applicant): Mammalian organs are built of a variety of intermingled cell types, the full extent and diversity of which are unknown. Specification and maintenance of cell identity, from a single cell embryo to any terminally differentiated cell such as an adult neuron, rely heavily on epigenetic mechanisms that act upon the genome to enable or prevent expression of specific sets of genes. In doing so, epigenetic regulation of gene expression enables a single genome to encode a diverse array of cell types in a multicellular organism. Epigenetic modifications ensure that a cell proceeds through a limited set of gene expression possibilities, and once differentiated, that a cell maintains its phenotype throughout its lifetime. As a consequence, disruption of epigenetic modification can result in a variety of diseases, including neurodevelopmental and psychiatric diseases, and cancer. We propose to develop a set of mouse transgenic tools that have the potential to transform the way epigenetic modifications can be studied and understood in this mammalian model system. The new tools will provide regulated expression of epigenetic modifiers in a variety of cell types and their progenitors, while permanently marking these cells or their progeny for examination at any later time point. Moreover, we will develop technology, in which a single locus in the mouse genome can be subjected to epigenetic perturbations in specific cells and at specific times in the animal's life. We will employ these tools to gain understanding of cell-type identity in the cortex as well as the mechanisms responsible for generating and maintaining this identity. Epigenetic regulators have been implicated in a number of brain diseases, and the tools we are developing will facilitate modeling or testing specific hypotheses that relate to perturbations of epigenetic phenomena. The insights gained may also provide guidance for the generation of specific cell types in vitro, and directions for 'repurposing' certain cell types in vivo. Although the focus of ur studies will be on the mouse brain, the versatile and modular design of our tools will enable their use in studying development, function or disease in any other tissue or cell type. We will ensure easy access to all tools we generate to maximize their impact on understanding various aspects of mammalian biology.

描述（由申请人提供）：哺乳动物的器官是由多种混杂的细胞类型构成的，其全部范围和多样性是未知的。从单细胞胚胎到任何最终分化的细胞（如成年神经元），细胞身份的规范和维持在很大程度上依赖于作用于基因组的表观遗传机制，以启用或阻止特定基因集的表达。这样，基因表达的表观遗传调控使单个基因组能够在多细胞生物中编码多种细胞类型。表观遗传修饰确保细胞通过一组有限的基因表达可能性，并且一旦分化，细胞在其一生中保持其表型。因此，表观遗传修饰的破坏可能导致各种疾病，包括神经发育和精神疾病以及癌症。我们建议开发一套小鼠转基因工具，这些工具有可能改变在哺乳动物模型系统中研究和理解表观遗传修饰的方式。新工具将在各种细胞类型及其祖细胞中提供表观遗传修饰因子的调控表达，同时永久标记这些细胞或其后代，以便在以后的任何时间点进行检查。此外，我们将开发技术，使小鼠基因组中的单个位点能够在动物生命的特定细胞和特定时间受到表观遗传扰动。我们将使用这些工具来了解皮层中的细胞类型身份以及负责产生和维持这种身份的机制。表观遗传调节因子与许多脑部疾病有关，我们正在开发的工具将有助于建模或测试与表观遗传现象扰动相关的特定假设。所获得的见解也可能为在体外产生特定细胞类型提供指导，以及在体内“重新利用”某些细胞类型的方向。虽然我们的研究重点将放在老鼠的大脑上，但我们工具的多功能和模块化设计将使他们能够