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.

项目摘要 我们靶向非编码基因组以获得治疗益处的能力存在根本性差距。而 虽然可药用基因组正在扩大，但它仍然局限于人类基因组编码的微小部分， 基因.这种对非编码基因组的排除是不幸的，因为这些区域可以提供一个强大的基因组。 dle精细控制细胞反应，比基因靶向方法更灵活。我们的长期 目标是对非编码基因组进行预测和功能性理解，这将阐明 这些区域如何成为基因组医学的特定靶点。为了实现这一长期目标， 这一建议的目的是系统地询问增强子基因调控的组合生物学。我们 将在三个层面上追求这一目标：从多种蛋白质效应物对单个增强子的作用， 多个增强子之间的协同性，并最终在基因组范围内协调多个增强子。 转录因子来影响细胞状态。我们开发了一个创新的平台， 组合基因调控的吞吐量评估，这将在这项建议中发挥核心作用。我们 总的假设是，在多个水平上，组合基因调控使用一小部分成分 to create创建a broad宽spectrum频谱of functionalities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，并检查每个组件单独和简单地 组合。所提出的研究的基本原理是， 基因调控将使非编码基因组的预测靶向基因组医学，导致在- 预防和治疗疾病的新方法。这一建议开辟了新的研究视野 理解组合基因调控的基本概念和表观遗传机制， 本发明涉及增强子功能的开发，以及调节增强子活性和工程化定制的改进方法 基因调控程序。最终，这些知识将被用于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。