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Regulation of Gene Enhancers in Human Heroin Use

人类海洛因使用中基因增强剂的调节

基本信息

批准号：
10306371
负责人：
YASMIN L. HURD
金额：
$ 26.7万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-15 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10306371
关键词：
ATAC-seq Acetylation Acquired Immunodeficiency Syndrome Affect Animal Model Autopsy Behavior Behavioral Binding Bioinformatics Brain Brain region Bromodomain Buprenorphine Caring Cell Nucleus Cells Cessation of life ChIP-seq Chromatin Chromatin Remodeling Factor Chromatin Structure Clinical Trials Communities Corpus striatum structure Data Data Set Development Disease Dorsal Drug Addiction Drug usage Enhancers Epidemic Epigenetic Process Family Fentanyl Functional disorder Gene Abnormality Gene Expression Gene Expression Regulation Gene Transfer Genes Genetic Transcription Genome Glutamates Government regulations Growth Guns Healthcare Systems Height Heroin Heroin Dependence Heroin Users Histone H3 Histones Human Immunity Inflammation Intervention Knowledge Link Maps Mediating Medical Methadone Modeling Molecular Morphology Neurobiology Neuroglia Neurons Nucleus Accumbens Opiate Addiction Opioid Opioid Analgesics Opioid replacement therapy Overdose Pathway interactions Patients Persons Pharmaceutical Preparations Pharmacology Population Program Research Project Grants Protein Family Proteins Public Health Rattus Regulation Regulatory Element Rodent Role Safety Sampling Self Administration Services Shock Substance Use Disorder Switch Genes Synaptic plasticity Testing Therapeutic Tissues Viral Work addiction automobile accident cancer therapy cell type chromatin modification chromatin remodeling clinical development drug addiction therapy drug of abuse gene network genetic regulatory protein genome-wide heroin abuser heroin use histone modification inhibitor insight knock-down member novel novel therapeutics opioid epidemic opioid overdose opioid use opioid use disorder overexpression prescription opioid screening small molecule social stigma targeted agent transcription factor transcriptome sequencing translational potential

项目摘要

PROJECT SUMMARY/ABSTRACT– PROJECT 4 Project 4’s objective is to characterize the influence of enhancer regions of the genome, which exert crucial control over gene expression, in opiate addiction. Work in several tissues has demonstrated that enhancer regions are “marked” by several specific histone modifications, such as H3K27ac (histone 3 Lys27 acetylation), and are enriched in several chromatin remodeling factors. One example is BRD4, a member of the BET (bromodomain and extra-terminal) subfamily, which binds acetylated histones through its bromodomains and is tightly linked with enhancers in several tissues. We have found elevated tissue levels of both H3K27ac and BRD4 in striatum of humans with heroin use disorders, with such elevations correlating strongly with years of heroin use and expression levels of key gene networks. Similar regulation is seen in striatum of rats that self-administer heroin. Moreover, we have found that small molecules that disrupt BRD4/BET function—in clinical development for cancer treatment—exert therapeutic-like effects in heroin addiction models in rodents. This Project will further these studies in several ways. We will obtain genome- wide maps of enhancer regions in NAc and DS of humans with heroin use disorders and matched controls, and in rats after heroin self-administration, by use of ChIP-seq for H3K27ac and BRD4, among other marks, in conjunction with the Gene and Chromatin Analysis Core. This will be performed separately on nuclei isolated from neurons and non-neuronal cells of these brain regions. We will work with the Core on advanced bioinformatics approaches to overlay these datasets, which is required for reliable identification of enhancers, along with RNA-seq and ATAC-seq datasets that we are currently generating on the same samples and that will provide further insight into the specific target genes affected by the identified heroin-regulated enhancers. We will test the causal role of enhancer regulation in heroin addiction by studying the effect of bidirectional manipulations of BRD4 in NAc and DS on gene expression and behavioral endpoints in rat models, including screening several BRD4/BET inhibitors for anti-addiction actions. These studies offer a translational opportunity to advance novel therapies for drug addiction.

项目摘要/摘要 - 项目 4 项目 4 的目标是表征基因组增强子区域的影响，这些区域发挥在阿片成瘾中对基因表达的关键控制。在多种组织中的工作表明增强子区域由几种特定的组蛋白修饰“标记”，例如 H3K27ac（组蛋白 3 Lys27）乙酰化），并富含多种染色质重塑因子。一个例子是 BRD4，它是 BET（溴结构域和额外末端）亚家族，通过其结合乙酰化组蛋白溴结构域并与多种组织中的增强子紧密相连。我们发现组织水平升高患有海洛因使用障碍的人类纹状体中 H3K27ac 和 BRD4 均存在，这种升高与与多年的海洛因使用和关键基因网络的表达水平密切相关。类似的规定见于自我注射海洛因的大鼠纹状体。此外，我们还发现，小分子可以破坏 BRD4/BET 功能——在癌症治疗的临床开发中——对海洛因发挥类似治疗作用啮齿动物成瘾模型。该项目将以多种方式进一步推进这些研究。我们将获得基因组- 患有海洛因使用障碍和匹配对照的人类 NAc 和 DS 中增强子区域的广泛图谱，在海洛因自我给药后的大鼠中，通过使用 ChIP-seq 检测 H3K27ac 和 BRD4 等标记，与基因和染色质分析核心结合使用。这将在分离的核上单独进行来自这些大脑区域的神经元和非神经元细胞。我们将与核心合作开发先进技术生物信息学方法覆盖这些数据集，这是可靠识别增强子所必需的，以及我们目前在相同样本上生成的 RNA-seq 和 ATAC-seq 数据集将进一步深入了解受已确定的海洛因调节增强剂影响的特定靶基因。我们将通过研究双向的作用来测试增强剂调节在海洛因成瘾中的因果作用 NAc 和 DS 中 BRD4 的操作对大鼠模型中基因表达和行为终点的影响，包括筛选几种 BRD4/BET 抑制剂的抗成瘾作用。这些研究提供了转化推进药物成瘾新疗法的机会。