Integrated, cell type specific functional genomics analyses of regulatory sequence elements and their dynamic interaction networks in neuropsychiatric brain tissues

神经精神脑组织中调节序列元件及其动态相互作用网络的综合、细胞类型特异性功能基因组学分析

• 批准号: 10133146
• 负责人: JOACHIM F HALLMAYER
• 金额: $ 164.33万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-20 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10133146
• 关键词: 3-Dimensional; ATAC-seq; Adult; Alleles; Anatomy; Autopsy; Biological Assay; Bipolar Disorder; Brain; Brain region; Cell Fraction; Cell Nucleus; Cells; Chromatin; Chromosomes; Code; Copy Number Polymorphism; Coupled; Critical Pathways; DNA; Data; Data Analyses; Databases; Development; Disease; Disease Marker; Disease Pathway; Early Diagnosis; Early Intervention; Elements; Freezing; Future; Gene Expression Profile; Genetic; Genetic Diseases; Genetic Transcription; Genome; Genomics; Goals; Haplotypes; Human; Human Development; Human Genome; Individual; Knowledge; Link; Longevity; Maps; Mass Spectrum Analysis; Mental disorders; Nature; Neuroglia; Neurons; Nuclear; Nuclear Protein; Nuclear Proteins; Nucleic Acid Regulatory Sequences; Organoids; Pathology; Pathway interactions; Patients; Pattern; Phase; Preventive care; Proteomics; Sampling; Schizophrenia; Series; Source; Stretching; Techniques; Technology; Time; Tissues; Untranslated RNA; Variant; autism spectrum disorder; bioinformatics tool; brain tissue; cell type; clinical phenotype; complex data; computational pipelines; design; epigenomics; fetal; functional genomics; genetic architecture; induced pluripotent stem cell; innovation; mind control; neuropsychiatric disorder; neuropsychiatry; novel; prenatal; psychiatric genomics; psychogenetics; rare variant; relating to nervous system; single-cell RNA sequencing; transcription factor; transcriptome; transcriptome sequencing; whole genome

Project Summary/Abstract After a century of debate about the fundamental nature of neuropsychiatric disorders, we know that genetics lie at their core, yet do not fully understand the critical underlying mechanisms of their disease-causing pathology. The overall goal of our proposal is the creation of comprehensive and integrated maps of chromatin accessibility, chromosome folding and transcriptional patterns, delineating regulatory regions in the genomes of key disease relevant anatomical regions of adult and fetal brains, in brains from patients with Schizophrenia, Autism Spectrum Disorder, Bipolar Affective Disorder and matched controls, and those with known CNVs (Copy-Number Variants) that may unmask regional or long-range targets of epigenomic regulatory interactions that may also be of great relevance in patients with the same clinical phenotype. We will use comprehensive and highly-resolving epigenomics assays, that were recently developed by us, and novel ways to integrate the data for the first time in neuropsychiatrically relevant brain tissues. We will generate comprehensive maps of the spectrum of organization and function of regulatory regions by integrating complementary techniques: single-cell ATAC-seq (scATAC-seq) to characterize chromatin openness and HiChIP to characterize long- range folding interactions of sorted neuronal and non-neuronal cells, both of which are coupled to single-cell RNA-seq and long-range RNA-seq for expression information, further complimented by information about transcription factors through proteomic analysis of nuclear fractions. These maps will then be combined with coding or non-coding/regulatory variants in the genomic sequence in the candidate regions and integrated into the overall PsychENCODE database, which will allow us to create and validate reference maps for epigenomic marks and interactions, determine aberrations to the reference state in patient tissue, and connect such aberrations to genetic disease loci as well as assemble such loci into disease pathways. This project will not only greatly expand our understanding of regulatory information encoded in the human genome and its impact on human brain development and neuropsychiatric disorders, but also produce the bioinformatics tools necessary to analyze the complex data being generated in PsychENCODE.

项目摘要/摘要 经过一个世纪关于神经精神疾病的基本本质的辩论，我们知道遗传学在 从他们的核心上讲，却不完全了解引起疾病的病理学的关键潜在机制。 我们建议的总体目标是创建染色质的全面和集成地图 可访问性，染色体折叠和转录模式，划定基因组中的调节区域 精神分裂症患者的大脑中，成人和胎儿大脑的关键疾病相关的解剖区域 自闭症谱系障碍，双相情感障碍和匹配的对照，以及具有已知CNV的患者 （拷贝数变体）可能会揭示表观基因质调节相互作用的区域或远程目标 这在具有相同临床表型的患者中也可能具有很大的意义。我们将使用综合 以及我们最近开发的高分辨率的表观基因组学测定法，以及整合的新方法 在神经精神上相关的脑组织中首次数据。我们将生成全面的地图 通过整合互补技术的组织和调节区域的组织和功能的范围： 单细胞ATAC-SEQ（SCATAC-SEQ）表征染色质的开放度和Hichip以表征长期 排序的神经元和非神经元细胞的范围折叠相互作用，两者都耦合到单细胞 用于表达信息的RNA-Seq和远程RNA-Seq，进一步称赞有关 通过核分数的蛋白质组学分析转录因子。这些地图将与 候选区域中基因组序列中的编码或非编码/调节变体，并整合到 整个Psychencode数据库，这将使我们能够为表观基因组创建和验证参考图 标记和互动，确定患者组织中参考状态的畸变，然后连接 遗传疾病基因座的畸变以及将这种基因座汇集到疾病途径中。这个项目不会 只有大大扩展了我们对人类基因组中编码的监管信息及其影响的理解 关于人脑发育和神经精神疾病，但也生产生物信息学工具 分析精神上生成的复杂数据所必需的。