Characterizing and Understanding Variation in Gene Regulatory Mechanisms Within and Between Species'

表征和理解物种内部和物种之间基因调控机制的变异

• 批准号: 10405511
• 负责人: Yoav Gilad
• 金额: $ 51.39万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10405511
• 关键词: Address; Biological Models; DNA Sequence; Gene Expression; Gene Expression Regulation; Genetic; Genomics; Human; Individual Differences; Modernization; Mutation; Noise; Pan Genus; Phenotype; Pongidae; Population; Property; Regulator Genes; Regulatory Element; Resolution; Technology; Trans-Activators; Transcript; Variant; cell type; human pluripotent stem cell; induced pluripotent stem cell; programs; protein expression

A central challenge in modern genomics is to decipher how DNA sequence encodes regulatory information, and how this is interpreted by trans-acting factors to produce cell type-specific programs of gene expression. We propose to use a variety of approaches and model systems to elucidate the genomic mechanisms that control spatially and temporally dynamic gene expression programs. To do so, we will use our recently established panels of induced pluripotent stem cells (iPSCs) from humans and chimpanzee, which allow us to perform dynamic and high-resolution studies of different gene regulatory phenotypes. We focus on addressing three complementary questions that allow us to study gene regulation using different perspectives: (i) Using evolutionary perspective, we ask what are the genetic and regulatory differences between humans and non-human apes? (ii) Using population perspective, we ask how do genetic changes in regulatory elements result in inter-individual differences in transcript and protein expression levels? (iii) Finally, focusing on a fundamental property of gene regulation, which until recently we were unable to study because of lack of suitable technology: We ask what is the genetic and mechanistic basis for the regulation of gene expression noise and robustness?

现代基因组学的一个核心挑战是破译 DNA 序列如何编码调控信息， 以及反式作用因子如何解释这一点以产生细胞类型特异性的基因表达程序。 我们建议使用各种方法和模型系统来阐明基因组机制 控制空间和时间动态基因表达程序。为此，我们将使用最近的 建立了来自人类和黑猩猩的诱导多能干细胞（iPSC）小组，这使我们能够 对不同基因调控表型进行动态和高分辨率研究。我们专注于 解决三个互补的问题，使我们能够使用不同的方法研究基因调控 观点：（i）使用进化观点，我们询问遗传和监管差异是什么 人类和非人类猿类之间？ (ii) 从群体的角度来看，我们询问基因变化是如何发生的 调控元件导致转录物和蛋白质表达水平的个体差异？ (三) 最后，关注基因调控的一个基本特性，直到最近我们还无法研究它 由于缺乏合适的技术：我们询问调节的遗传和机制基础是什么 基因表达噪音和鲁棒性？