Three Dimensional Chromosome Architecture in Drug Addiction

毒瘾中的三维染色体结构

• 批准号: 10401842
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10401842
• 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.

项目摘要 /摘要 神经功能需要对环境刺激的响应进行准确控制基因转录。 异常基因表达被认为会促进吸毒成瘾。因此，研究基因的调节 药物成瘾中的表达可能会为这种疾病提供机械见解，但仍提供有限的 治疗的选择，代表了巨大的社会和经济负担。据估计有 哺乳动物基因组中的一百万个监管元素，它们通常位于距离 他们的靶基因。尽管下一代测序的最新发展提供了大规模 调节性DNA元件的鉴定，它们调节的基因仍然在很大程度上未知。最近， 线性DNA进入核的有序压实和组织已被认为具有 通过促进基因启动子与远端之间的相互作用，对基因转录的主要影响 监管要素。但是，如何在大脑中组织这种三维染色质结构 它的变化方式，尤其是在吸毒中，仍然是晦涩的。在这里，我们建议研究长期 远端DNA元件与所有带注释的小鼠基因启动子之间的范围循环相互作用 特定的神经元亚型差异化成瘾。为了实现这一目标，我们将应用切割 边缘启动子捕获HI-C技术介绍了D1和D2-培养基中的整个启动子Interactome 伏隔核中的棘神经元（MSN），脑奖励结构。我们还将检查 可卡因和海洛因上瘾小鼠的神经元亚型特异性高阶基因组组织。我们 预计会阐明神经元亚型特异性和药物特异性三维染色体 架构变化。这些变化中有许多可能涉及先前鉴定的遗传变异位点 啮齿动物和人之间的保守。操纵这些监管区域不仅可能改变 调节其靶基因的表达，但也可能改变相关的成瘾行为。之上 完成，我们的研究不仅无疑会提高我们对吸毒成瘾的理解 基因组架构组织的未完成的维度，它还将为合理的新途径打开新的途径 操纵该疾病，该疾病具有未来治疗应用的潜在效用。

项目成果

DNA Methyltransferase 3A Is Involved in the Sustained Effects of Chronic Stress on Synaptic Functions and Behaviors.

• DOI: 10.1093/cercor/bhaa337
• 发表时间: 2020-11
• 期刊: Cerebral cortex
• 影响因子: 3.7
• 作者: Jing Wei;Jia Hua Cheng;Nicholas J. Waddell;Zi-Jun Wang;Xiaodong Pang;Qing Cao;Aiyi Liu;Javed M. Chitam

DNA Epigenetics in Addiction Susceptibility.

• DOI: 10.3389/fgene.2022.806685
• 发表时间: 2022
• 期刊: Frontiers in genetics
• 影响因子: 3.7
• 作者: Kaplan G;Xu H;Abreu K;Feng J
• 通讯作者: Feng J

Role of Long Noncoding RNA Gas5 in Cocaine Action.

• DOI: 10.1016/j.biopsych.2020.05.004
• 发表时间: 2020-11-15
• 期刊: Biological psychiatry
• 影响因子: 10.6
• 作者: Xu H;Brown AN;Waddell NJ;Liu X;Kaplan GJ;Chitaman JM;Stockman V;Hedinger RL;Adams R;Abreu K;Shen L;Neve R;Wang Z;Nestler EJ;Feng J
• 通讯作者: Feng J

Whole Genome DNA Methylation Profiling of D2 Medium Spiny Neurons in Mouse Nucleus Accumbens Using Two Independent Library Preparation Methods.

• DOI: 10.3390/genes13020306
• 发表时间: 2022-02-06
• 期刊: Genes
• 影响因子: 3.5
• 作者: Li Y;Xu H;Chitaman JM;Feng J
• 通讯作者: Feng J