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: 10609543
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609543
• 关键词: 3-Dimensional; ATAC-seq; Adult; Alleles; Autopsy; Biological Assay; Bipolar Disorder; Brain; Brain region; Cell Fraction; Cell Nucleus; Cells; Chromatin; Chromosome Mapping; Chromosomes; Code; Copy Number Polymorphism; Coupled; Critical Pathways; DNA; DNA mapping; Data; Data Analyses; Databases; Development; Dimensions; 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; Regional Anatomy; Sampling; Schizophrenia; Series; Sorting; Source; Stretching; Techniques; Technology; Time; Tissues; Untranslated RNA; Variant; autism spectrum disorder; bioinformatics tool; brain tissue; cell type; clinical phenotype; complex data; computational pipelines; data integration; design; epigenomics; fetal; functional genomics; genetic architecture; induced pluripotent stem cell; innovation; mind control; neural; neuropsychiatric disorder; neuropsychiatry; novel; prenatal; psychiatric genomics; psychogenetics; rare variant; 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.

项目概要/摘要 经过一个世纪关于神经精神疾病的基本性质的争论后，我们知道遗传学谎言 其核心，但尚未完全了解其致病病理学的关键潜在机制。 我们提案的总体目标是创建全面且集成的染色质图谱 可及性、染色体折叠和转录模式、描绘基因组中的调控区域 成人和胎儿大脑的关键疾病相关解剖区域，精神分裂症患者的大脑， 自闭症谱系障碍、双向情感障碍和匹配对照，以及具有已知 CNV 的对照 （拷贝数变体）可能揭示表观基因组调控相互作用的区域或远程目标 这对于具有相同临床表型的患者也可能具有很大的相关性。我们将综合运用 和我们最近开发的高分辨率表观基因组学检测，以及整合 首次在神经精神相关的脑组织中获得数据。我们将生成综合地图 通过整合互补技术来扩大监管区域的组织和功能范围： 单细胞 ATAC-seq (scATAC-seq) 表征染色质开放性，HiChIP 表征长链 排序的神经元和非神经元细胞的范围折叠相互作用，两者都与单细胞偶联 用于表达信息的 RNA-seq 和长程 RNA-seq，并进一步得到以下信息的补充 通过核组分的蛋白质组学分析转录因子。然后这些地图将与 候选区域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，这将使我们能够创建和验证表观基因组的参考图谱 标记和相互作用，确定患者组织中参考状态的像差，并将这些 遗传疾病基因座的畸变以及将这些基因座组装成疾病途径。该项目不会 只会极大地扩展我们对人类基因组中编码的监管信息及其影响的理解 对人类大脑发育和神经精神疾病的研究，还产生生物信息学工具 分析 PsychENCODE 中生成的复杂数据所必需的。