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进行治疗益处的能力存在基本差距。而 可吸毒基因组正在扩展，它仍然局限于编码的人类基因组的一小部分 基因。非编码基因组的这种排除是不幸的，因为这些地区可以提供强大的汉义 DLE可以很好地控制细胞反应，并且比靶向基因的方法更灵活。我们的长期 目标是对非编码基因组有一种预测和功能理解，该理解将阐明 这些区域如何专门针对基因组医学。达到这个长期目标，objec- 该建议是系统地询问增强子基因调节的组合生物学。我们 将在三个层面上追求这一目标：从多种蛋白质效应子对单个增强剂的作用到 多个增强子之间的合作性，并在多个基因组的协调中达到顶点 影响细胞状态的转录因子。我们已经开发了一个创新平台，可以使 组合基因调节的吞吐量评估，该评估将在该提案中起核心作用。我们的 总体假设是，在多个级别上，组合基因调节使用了一小部分组件 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成部分来解释联系，并检查每个关键组成部分 组合。拟议研究的理由是对组合的基本理解 基因调节将使非编码基因组的预测靶向基因组医学，从而导致 新的预防和治疗疾病的方法。该提案打开了新的研究视野 了解组合基因调节的潜在概念和表观遗传机制 衍生增强器功能，以及改进的方法来调节增强器活动和工程师自定义 基因调节计划。最终，将需要这些知识来利用基因组进行工程学 并了解非编码调节剂如何促进发展和疾病。