Genomic organization of long-distance gene regulation

长距离基因调控的基因组组织

• 批准号: 9142702
• 负责人: Matthew Thomas Maurano
• 金额: $ 42.38万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-22 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9142702
• 关键词: Address; Affect; Animal Mammary Glands; DNA; Disease; Distal; Distant; Elements; Epigenetic Process; Explosion; Gene Expression Regulation; Gene Targeting; Genes; Genetic Variation; Genome; Genomics; Histocompatibility Testing; Human; Human Genetics; Human Genome; Introns; Link; Public Health; Regulation; Regulatory Element; Research; Specific qualifier value; Structure; System; Time; Transcriptional Regulation; Untranslated RNA; Variant; Work; abstracting; cell type; falls; gene therapy; genome editing; genome-wide; improved; mammalian genome; promoter; trait

Project Abstract Common-disease associated variants systematically localize to the regulatory DNA of specific cell and tissue types, suggesting that the genome-wide activity of regulatory elements can provide key epigenetic context for the interpretation of genetic variation. However, regulatory elements in mammalian genomes are exquisitely sensitive to genomic context and often regulate distant genes. Thus, interpretation of the functional conse- quences of sequence variation at non-coding regulatory elements has been impeded by the lack of a mecha- nistic understanding of genomic regulatory structure and the sequence determinants of long-range interaction. I propose an experimental and computational research plan to address this pressing problem, focusing on four fundamental questions: Do sequence features of distal regulatory elements specify interaction with nearby promoters? To what extent do intervening sequence elements affect long-distance interaction genome-wide? Is long-distance interaction organized into functional domains in mammalian genomes? Do regulatory elements act in modular combinations of reducible activities, or do they instead form constellations of emergent regulato- ry function? This work will dramatically extend our understanding of the genomics of transcriptional regulation, facilitating systems-level analyses of common disease-associated variation in human genomes and industrial applications for genome editing and gene therapy.

项目摘要 常见疾病相关变异体系统地定位于特定细胞和组织的调控DNA 类型，这表明调控元件的全基因组活性可以提供关键的表观遗传学背景 对遗传变异的解释。然而，哺乳动物基因组中的调控元件是精致的 对基因组环境敏感，经常调节遥远的基因。因此，对功能概念的解释-- 由于缺乏一种机制，非编码调控元件上的序列变异受到阻碍。 对基因组调控结构和远程相互作用的序列决定因素的本能理解。我 提出一个实验和计算研究计划来解决这个紧迫的问题，重点放在四个方面 基本问题：远端调控元件的序列特征是否指定了与附近的相互作用 推动者？介入序列元件在多大程度上影响全基因组范围内的远距离相互作用？是 哺乳动物基因组中组织成功能区的长距离相互作用？监管要素是否 以可减少的活动的模块组合起作用，还是它们形成了新出现的调节的星座-- RY功能？这项工作将极大地扩展我们对转录调控基因组学的理解， 促进对人类基因组和工业中常见疾病相关变异的系统水平分析 基因组编辑和基因治疗的应用。