Cell Specificity of the Human Heroin Epigenome

人类海洛因表观基因组的细胞特异性

• 批准号: 10159879
• 负责人: STELLA DRACHEVA
• 金额: $ 53.82万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10159879
• 关键词: Acetylation; Adult; Animal Model; Animals; Astrocytes; Autopsy; Behavior; Behavioral; Brain; Brain Mapping; Brain region; Brain-Derived Neurotrophic Factor; Cell Nucleus; Cells; Cessation of life; ChIP-seq; Chromatin; Communities; Control Animal; DNA Methylation; Data; Data Set; Development; Down-Regulation; Drug Addiction; Drug Exposure; Enhancers; Epidemic; Epigenetic Process; Exposure to; Functional disorder; Gene Expression; Genes; Genetic; Genetic Transcription; Glutamates; Heroin; Heroin Abuse; Heroin Dependence; Heterogeneity; Human; Human Genome; Individual; Interneurons; Knowledge; Learning; Link; Literature; Lysine; Maps; Memory; Methylation; Microglia; Modification; Molecular; NPAS4 gene; Nervous system structure; Neuroglia; Neurons; Nucleic Acid Regulatory Sequences; Oligodendroglia; Opiate Addiction; Output; Pharmaceutical Preparations; Population; Positioning Attribute; Predisposition; Prefrontal Cortex; Rattus; Regulator Genes; Regulatory Element; Research; Role; Sampling; Self Administration; Specificity; Synapses; Synaptic plasticity; Testing; Time; Tissues; Transforming Protein ERG; Untranslated RNA; Viral; Work; addiction; aged; base; bead chip; brain cell; cell type; clinical development; drug maintenance; effective therapy; efficacious treatment; epigenetic regulation; epigenetic variation; epigenome; experience; frontal lobe; gamma-Aminobutyric Acid; gene repression; genome resource; genome-wide; heroin abuser; histone modification; human imaging; imaging study; in vivo; innovation; novel; novel therapeutic intervention; opioid abuse; opioid overdose; promoter; relating to nervous system; transcriptome; transcriptome sequencing

Project Summary Opiate abuse and overdose have risen to epidemic proportions in the USA in recent years. Only limited medication options are currently available, which is in large part due to the surprising lack of knowledge about the pathophysiologic mechanisms that underlie opiate addiction. Recent animal studies have provided robust evidence that repeated drug exposure induces changes in gene expression through alterations in epigenetic regulation that are linked to addiction-related behavioral abnormalities. However, information about the epigenetic landscape in the brains of human addicts remains limited and is critical for the development of clinically effective treatments. Recent studies have achieved a comprehensive mapping of brain-specific epigenetic marks in the human genome using homogenate postmortem tissue. However, cellular heterogeneity of the brain precludes a reliable annotation of cell-type-specific epigenetic modifications from these data. Aim1 of this project will leverage our newly developed molecular strategies to illuminate the neural subtype-specific epigenome of heroin addiction with unprecedented detail—in four different populations of brain cells—which will highly enhance the likelihood of identifying cell-type-specific signatures of addiction-associated epigenetic variations. Our recent epigenetic studies in glutamatergic (Glu) projection neurons and inhibitory GABA interneurons from the human orbital frontal cortex (OFC) suggest that many activity-dependent genes (ADGs) are “poised” to be activated in a neuron-subtype-specific manner. ADGs are activated by experience-driven synaptic activity (including exposure to addictive drugs) and regulate diverse aspects of the nervous system, (including synaptic plasticity). Notably, our recent RNA-seq data in homogenate OFC samples showed that among the most significant changes is the downregulation of a subset of the ADGs. These results are in line with the growing body of literature that implicates diminished output from the ventral aspects of the prefrontal cortex in drug addiction. We hypothesize that the steady-state expression and inducibility of the ADGs (the latter is determined by their epigenetic milieu) are altered in heroin addicts in a neuron-subtype-specific manner, and we will test this hypothesis in Aim 2. Considering the importance of ADGs in synaptic plasticity that accompanies the development and maintenance of drug addiction, in Aim 2 we will utilize a translational animal model to explore the cell-specific functional contribution of ADGs to heroin self-administration behavior. Overall, this innovative line of research will develop unique datasets that will be available to the research community and will provide an urgently needed resource for genome-wide neural subtype-specific chromatin and transcriptome maps in heroin abuse and normal subjects. Moreover, the mechanistic studies in animal models can promote the development of novel therapeutic interventions.

项目概要 近年来，阿片类药物滥用和过量服用已成为美国流行病。仅限有限 目前有可用的药物选择，这在很大程度上是由于对以下方面的了解令人惊讶地缺乏 阿片成瘾的病理生理机制。最近的动物研究提供了强有力的证据 有证据表明，反复接触药物会通过表观遗传的改变诱导基因表达的变化 与成瘾相关的行为异常有关的监管。然而，有关信息 人类成瘾者大脑中的表观遗传景观仍然有限，对于成瘾者的发展至关重要 临床上有效的治疗方法。 最近的研究已经实现了大脑特异性表观遗传标记的全面绘制。 使用匀浆死后组织的人类基因组。然而，大脑的细胞异质性排除了 从这些数据中对细胞类型特异性表观遗传修饰进行可靠注释。该项目的目标1将 利用我们新开发的分子策略来阐明神经亚型特异性表观基因组 海洛因成瘾在四个不同的脑细胞群中具有前所未有的细节，这将高度 提高识别成瘾相关表观遗传变异的细胞类型特异性特征的可能性。 我们最近对谷氨酸能 (Glu) 投射神经元和抑制​​性 GABA 的表观遗传学研究 来自人类眶额皮质（OFC）的中间神经元表明许多活动依赖性基因（ADG） “准备好”以神经元亚型特异性的方式被激活。 ADG 由经验驱动激活 突触活动（包括接触成瘾药物）并调节神经系统的各个方面， （包括突触可塑性）。值得注意的是，我们最近在匀浆 OFC 样本中的 RNA-seq 数据表明 最显着的变化之一是部分每日总目标的下调。这些结果符合 随着越来越多的文献表明前额叶腹侧的输出减少 皮质在药物成瘾中的作用。我们假设 ADG 的稳态表达和诱导能力（ 后者由其表观遗传环境决定）在海洛因成瘾者中以神经元亚型特异性发生改变 方式，我们将在目标 2 中检验这一假设。考虑 ADG 在突触可塑性中的重要性 伴随着毒瘾的发展和维持，在目标 2 中，我们将利用转化 动物模型探索 ADG 对海洛因自我给药行为的细胞特异性功能贡献。 总体而言，这一创新研究领域将开发独特的数据集，可供 研究界将为全基因组神经亚型特异性提供迫切需要的资源 海洛因滥用和正常受试者的染色质和转录组图谱。此外，机理研究 动物模型可以促进新型治疗干预措施的发展。

项目成果

Evolution of regulatory signatures in primate cortical neurons at cell-type resolution.

• DOI: 10.1073/pnas.2011884117
• 发表时间: 2020-11-10
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Kozlenkov A;Vermunt MW;Apontes P;Li J;Hao K;Sherwood CC;Hof PR;Ely JJ;Wegner M;Mukamel EA;Creyghton MP;Koonin EV;Dracheva S
• 通讯作者: Dracheva S

Common schizophrenia risk variants are enriched in open chromatin regions of human glutamatergic neurons.

• DOI: 10.1038/s41467-020-19319-2
• 发表时间: 2020-11-04
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Hauberg ME;Creus-Muncunill J;Bendl J;Kozlenkov A;Zeng B;Corwin C;Chowdhury S;Kranz H;Hurd YL;Wegner M;Børglum AD;Dracheva S;Ehrlich ME;Fullard JF;Roussos P
• 通讯作者: Roussos P