A Big Data Approach to Identify Epigenetic, Transcriptomic, and Network Dynamics as Immune Dysfunction Drivers Associated with HIV Infection and Substance Use Disorder

项目摘要 阿片类药物危机于2017年被宣布为公共卫生紧急事件。这导致了 阿片类药物过量、注射剂使用以及最终艾滋病毒的发生率增加 传输美国有超过171，000人因艾滋病毒感染而感染艾滋病毒， 物质使用障碍（SUD）。尽管已知的事实是，艾滋病毒和SUD显着 干扰先天免疫和适应性免疫，它们的潜在分子机制， 与免疫功能障碍的相互作用尚未被探索。综合功能 单细胞分辨率的表征对于提供新的分子见解至关重要， 发现治疗靶点。 新测序技术的最新进展和社区努力分享 基因组数据提供了前所未有的机会，了解分子动力学 免疫功能障碍增加HIV感染和SUD。本申请描述了 整合策略和机器学习方法来联合收割机新的分析（如STARR- seq）与高维度、多尺度基因组谱一起阐明转录， 表观遗传和网络改变以及与HIV相关的关键免疫功能障碍驱动因素 的SUD。具体而言，我们将（1）将新的功能基因组学检测与单细胞 多组学数据构建细胞类型特异性多模式基因调控网络（GRNs）， （2）为受艾滋病毒/SUD影响的人建立一个全面的免疫分析数据中心 个体并构建疾病和细胞类型特异性GRNs，（3）揭示关键网络如何 HIV感染和/或SUD后TF的变化和异常行为可导致免疫功能低下， 功能障碍与现有的专注于转录组分析的努力不同，这项拟议的工作 提出了一种真正新颖的大数据方法，用于建模基因调控和研究 通过以单细胞分辨率整合异质多组学特征来评估疾病风险因素。 由此产生的顺式调控元件在单细胞分辨率的全面名单将扩大 已知功能区的数量。构建的免疫细胞图谱、GRNs和鉴定 免疫功能障碍的关键驱动因素将通过网络服务和注释向公众开放 数据库。我们的综合计算成果将以分布式开源的方式发布 程序.总而言之，我们释放的资源将加速更广泛的科学领域的研究。 社区通过提供必要的工具来研究免疫功能，这将有利于其他 研究人员探索HIV和/或SUD免疫系统功能的遗传基础。

PROJECT ABSTRACT The opioid crisis was declared a public health emergency in 2017. It has led to an increased incidence of opioid overdose, injection substance use, and, eventually, HIV transmission. More than 171,000 people in the United States are living with HIV as a result of substance use disorder (SUD). Despite the known fact that both HIV and SUD significantly disturbs both innate immunity and adaptive immunity, their underlying molecular mechanisms, and interplay to immune dysfunction remain unexplored. Comprehensive functional characterization at a single-cell resolution is essential to provide new molecular insights and discover therapeutic targets. Recent advances in novel sequencing technologies and community efforts to share genomic data provide unprecedented opportunities to understand the molecular dynamics of immune dysfunction up HIV infection and SUD. This application describes the development of integrative strategies and machine learning methods to combine novel assays (such as STARR- seq) with high-dimensional, multi-scale genomic profiles to elucidate the transcriptional, epigenetic, and network alterations and to key immune dysfunction drivers associated with HIV and SUD. Specifically, we will (1) Integrate novel functional genomics assays with single-cell multi-omics data to construct cell-type-specific multi-modal gene regulatory network (GRNs) in healthy individuals, (2) build a comprehensive immune profiling data hub for HIV/SUD-affected individuals and construct disease- and cell-type-specific GRNs, (3) uncover how key network changes and aberrant behaviors of TFs upon HIV infection and/or SUD can lead to immune dysfunction. Distinct from existing efforts focusing on transcriptome analyses, this proposed work presents a genuinely novel big-data approach for both modeling gene regulation and investigating disease-risk factors by incorporating heterogeneous multi-omics profiles at a single-cell resolution. The resultant comprehensive list of cis-regulatory elements at a single-cell resolution will expand the number of known functional regions. The constructed immune cell atlas, GRNs, and identify key drivers of immune dysfunction will be accessible to the public via web services and annotation databases. Our integrative computational efforts will be released distributed open-source programs. Altogether, our released resource will accelerate research in the broader scientific community by providing essential tools to investigate immune function, which will benefit other investigators exploring the genetic underpinnings of immune system function of HIV and/or SUD.