Three Dimensional Chromosome Architecture in Drug Addiction

毒瘾中的三维染色体结构

• 批准号: 10159232
• 负责人: Jian Feng
• 金额: $ 46.2万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10159232
• 关键词: 3-Dimensional; Architecture; Behavior; Brain; Cell Nucleus; Chromatin; Chromosomes; Cocaine; DNA; Development; Dimensions; Disease; Distal; Drug Addiction; Economic Burden; Elements; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genetic Variation; Genome; Heroin; Hi-C; Human; Mus; Neurons; Neurophysiology - biologic function; Nucleic Acid Regulatory Sequences; Nucleus Accumbens; Pharmaceutical Preparations; Regulation; Regulatory Element; Rewards; Rodent; Site; Stimulus; Structure; Technology; Therapeutic; Transcriptional Regulation; addiction; insight; mammalian genome; next generation sequencing; novel; promoter; response; social

PROJECT SUMMARY / ABSTRACT Neural function requires accurate control of gene transcription in response to environmental stimuli. Aberrant gene expression is believed to drive drug addiction. Therefore, studying the regulation of gene expression in drug addiction may provide mechanistic insights to this disease, which still offers limited options for treatment and represents a vast social and economic burden. It is estimated that there are up to one million regulatory elements in the mammalian genome, which are often located great distances from their target genes. Although recent developments in next generation sequencing have provided large-scale identification of regulatory DNA elements, which genes they regulate remains largely unknown. Recently, the ordered compaction and organization of linear DNA into the nucleus has been recognized as having a major influence on gene transcription by facilitating interactions between gene promoters and distal regulatory elements. However, how this three-dimensional chromatin architecture is organized in the brain and how it is changed, particularly in drug addiction, is still obscure. Here we propose to study the long- range looping interactions between distal DNA elements and all annotated mouse gene promoters within the specific neuronal subtypes differentially engaged in addiction. To achieve this, we will apply the cutting edge promoter capture Hi-C technology to profile the entire promoter interactome in D1- and D2- medium spiny neurons (MSNs) in nucleus accumbens, the key brain reward structure. We will also examine the neuron subtype-specific higher order genome organization in both cocaine and heroin addicted mice. We anticipate to elucidate neuron subtype specific and drug specific three-dimensional chromosome architecture changes. Many of these changes may involve previously identified genetic variation sites conserved between rodents and human. Manipulation of these regulatory regions may not only alter regulation of their target gene's expression, but may also change the associated addiction behaviors. Upon completion, our study will not only indisputably advance our understanding of drug addiction to the unachieved dimension of genome architecture organization, it will also open a new avenue to a plausible manipulation of the disease, which has potential utility for future therapeutic applications.

项目总结/摘要 神经功能需要精确控制基因转录以响应环境刺激。 基因表达异常被认为是导致药物成瘾的原因。因此，研究基因的调控 药物成瘾中的表达可能为这种疾病提供机制性的见解， 治疗选择并带来巨大的社会和经济负担。据估计， 哺乳动物基因组中有100万个调控元件，这些元件通常位于距离 他们的目标基因。尽管下一代测序的最新发展已经提供了大规模的测序技术， 鉴定调节DNA元件，它们调节哪些基因仍然是未知的。最近， 线性DNA有序地压缩和组织到细胞核中被认为具有 通过促进基因启动子和远端之间的相互作用对基因转录产生重要影响 监管要素。然而，这种三维染色质结构在大脑中是如何组织的， 以及它是如何改变的，特别是在药物成瘾方面，仍然不清楚。在这里，我们建议研究长期- 远端DNA元件和所有注释的小鼠基因启动子之间的范围环相互作用， 特定的神经元亚型与成瘾有着不同的关系。为了实现这一点，我们将应用切割 边缘启动子捕获Hi-C技术，用于在D1和D2培养基中分析整个启动子相互作用组 棘神经元（MSNs）位于脑桥核，这是大脑的关键奖赏结构。我们亦会研究 可卡因和海洛因成瘾小鼠的神经元亚型特异性高阶基因组组织。我们 有望阐明神经元亚型特异性和药物特异性的三维染色体 架构变化。许多这些变化可能涉及以前确定的遗传变异位点 在啮齿动物和人类之间是保守的。对这些调控区域的操纵不仅可以改变 调节其靶基因的表达，但也可能改变相关的成瘾行为。后 完成后，我们的研究不仅将无可争议地推进我们对药物成瘾的理解， 基因组结构组织的未实现的维度，它也将开辟一条新的途径， 操纵疾病，这对未来的治疗应用具有潜在的效用。