Combinatorial Biology of Gene Regulation for Cellular Engineering

细胞工程基因调控的组合生物学

• 批准号: 9349247
• 负责人: Gary Chung Hon
• 金额: $ 239.33万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9349247
• 关键词: Biology; Cells; Custom; Development; Disease; Engineering; Enhancers; Epigenetic Process; Exclusion; Gene Expression Regulation; Gene Targeting; Genes; Genetic Transcription; Genome; Genome engineering; Genomic medicine; Goals; Human Genome; Human body; Individual; Knowledge; Maintenance; Methods; Play; Prevention approach; Proteins; Regulator Genes; Regulatory Element; Research; Role; Therapeutic; Untranslated RNA; cellular engineering; combinatorial; disorder risk; flexibility; genome-wide; improved; innovation; programs; response; transcription factor

Project summary There is a fundamental gap in our ability to target the non-coding genome for therapeutic benefit. While the druggable genome is expanding, it still remains confined to the tiny fraction of the human genome encoding for genes. This exclusion of the non-coding genome is unfortunate, as these regions can provide a powerful han- dle to finely control cellular responses and are more flexible than gene-targeting approaches. Our long-term goal is to develop a predictive and functional understanding of the non-coding genome, which will elucidate how these regions can be specifically targeted for genomic medicine. Towards this long-term goal, the objec- tive of this proposal is to systematically interrogate the combinatorial biology of enhancer gene regulation. We will pursue this objective at three levels: from the action of multiple protein effectors on individual enhancers, to the cooperativity between multiple enhancers, and culminating in the genome-wide coordination of multiple transcription factors to influence cell state. We have developed an innovative platform that enables high throughput assessment of combinatorial gene regulation, which will play a central role in this proposal. Our overall hypothesis is that, across multiple levels, combinatorial gene regulation uses a small set of components to create a broad spectrum of functionalities. We further hypothesize that the rules governing these functionali- ties can be explained by defining the key components, and examining how each functions alone and in simple combinations. The rationale for the proposed research is that a fundamental understanding of combinatorial gene regulation will enable predictive targeting of the non-coding genome for genomic medicine, leading to in- novative approaches to the prevention and treatment of disease. This proposal opens new research horizons to understanding the underlying concepts of combinatorial gene regulation and the epigenetic mechanisms un- derlying enhancer function, and for improved methods to modulate enhancer activity and engineer custom gene regulatory programs. Ultimately, this knowledge will be required to harness the genome for engineering and to understand how non-coding regulators contribute to development and disease.

项目概要 我们靶向非编码基因组以获得治疗效果的能力存在根本性差距。虽然 可药物基因组正在扩大，但它仍然局限于编码人类基因组的一小部分 基因。这种非编码基因组的排除是不幸的，因为这些区域可以提供强大的汉- 可以精细地控制细胞反应，并且比基因靶向方法更灵活。我们的长期 目标是发展对非编码基因组的预测性和功能性理解，这将阐明 如何专门针对这些区域进行基因组医学。为实现这一长期目标，目标 该提案的目的是系统地探讨增强子基因调控的组合生物学。我们 将在三个层面上实现这一目标：从多种蛋白质效应子对单个增强子的作用，到 多个增强子之间的协同作用，并最终导致多个增强子的全基因组协调 影响细胞状态的转录因子。我们开发了一个创新平台，可以实现高 组合基因调控的通量评估，这将在该提案中发挥核心作用。我们的 总体假设是，在多个层面上，组合基因调控使用一小组组件 创建广泛的功能。我们进一步假设管理这些功能的规则 可以通过定义关键组件并检查每个组件如何单独且简单地发挥作用来解释联系 组合。拟议研究的基本原理是对组合的基本理解 基因调控将使基因组医学的非编码基因组的预测目标成为可能，从而导致 预防和治疗疾病的创新方法。该提案开辟了新的研究视野 了解组合基因调控的基本概念和表观遗传机制 深入的增强子功能，以及调节增强子活性和工程定制的改进方法 基因调控计划。最终，需要这些知识来利用基因组进行工程 并了解非编码调节因子如何促进发育和疾病。