Genomic organization of long-distance gene regulation

项目摘要 常见疾病相关的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背景， 遗传变异的解释。然而，哺乳动物基因组中的调控元件 对基因组环境敏感，并且经常调节远距离基因。因此，对功能性结论的解释- 在非编码调控元件上的序列变异的序列由于缺乏机制而受到阻碍， 对基因组调控结构和长距离相互作用的序列决定因素的理性理解。我 提出一个实验和计算研究计划，以解决这一紧迫的问题，重点是四个 基本问题：远端调控元件的序列特征是否指定了与附近调控元件的相互作用？ 促销员？间插序列元件在多大程度上影响全基因组的长距离相互作用？是 长距离相互作用组织成哺乳动物基因组中的功能域？监管要素 它们是以可还原活动的模块化组合的形式起作用，还是形成了涌现的调节器的星座， 函数？这项工作将极大地扩展我们对转录调控基因组学的理解， 促进人类基因组和工业中常见疾病相关变异的系统级分析 用于基因组编辑和基因治疗。

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.