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.

项目总结/文摘