Charting the 3D epigenome in human brain development and diseases

绘制人类大脑发育和疾病中的 3D 表观基因组图

基本信息

批准号：
10116735
负责人：
ARNOLD KRIEGSTEIN
金额：
$ 63.64万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10116735
关键词：
3-Dimensional ATAC-seq Adolescence Adolescent Affect Age Architecture Astrocytes Biological Biological Process Biological Testing Brain Budgets Cell Lineage Cell Maturation Cells Chromatin Chromatin Loop Collection Communities Data Data Set Development Disease Distal Elements Fluorescence-Activated Cell Sorting Funding Future Gene Expression Gene Expression Regulation General Population Genes Genetic Genetic Transcription Genetic study Goals Health Human Human Genome Interneurons Knowledge Ligation Link Maps Medical Genetics Methods Microglia Modeling Nature Neonatal Neuroglia Neurons Newborn Infant Nucleic Acid Regulatory Sequences Pathway interactions Patients Phenotype Population Prefrontal Cortex Radial Regulatory Element Research Resources Sampling Second Pregnancy Trimester Single Nucleotide Polymorphism in Regulatory Sequence Testing Third Pregnancy Trimester Trans-Omics for Precision Medicine Transcriptional Regulation United States National Institutes of Health Untranslated RNA Validation Variant Work autism spectrum disorder cell type data integration epigenome epigenomics excitatory neuron genetic resource genetic variant genome wide association study genomic locus in vivo induced pluripotent stem cell infancy insight member neurodevelopment neuropsychiatric disorder neuropsychiatry oligodendrocyte lineage personalized medicine promoter stem cells three dimensional structure transcriptome transcriptomics

项目摘要

Project Summary Cis-regulatory elements control Cell-type-specific gene regulation via looping with their targeting genes. Therefore, mapping the 3D chromatin interactions between promoters and cis-regulatory elements will be pivotal to understand the functions of regulatory regions. Besides, many genetic variants associated with neuropsychiatric diseases reside in the putative cis-regulatory elements. They may contribute to disease by affecting regulatory sequences function, but the exact mechanisms of how they contribute to diseases via gene regulation remain unknown. Here, we aim to make substantial advances in understanding how the 3D epigenome contributes to brain development and diseases by mapping and analyzing the dynamic changes during the human prefrontal cortex development. We will first map transcriptome, chromatin accessibility, and 3D chromatin loops in six distinct cell types from the developing prefrontal cortex and perform an integrative analysis to interrogate how chromatin interaction control gene expression and development. Second, we will integrate the 3D epigenomic datasets with medical genetics resources to gain insights into cell types, genomic loci, and biological pathways that are causal to diseases, link GWAS SNPs with their target genes. Third, to establish cell-type-specific functional links between chromatin loops and target gene expression, we will test the biological consequences of distal regulatory regions interacting with promoters in iPSC models and primary cells. Our project will reveal new insight into the biological functions of the 3D epigenome in brain development and diseases.

项目摘要顺式调节元件通过其靶向基因循环控制细胞类型的特异性基因调节。因此，映射启动子和顺式调节元素之间的3D染色质相互作用将是关键了解监管区域的功能。此外，许多遗传变异神经精神疾病存在于推定的顺式调节元素中。他们可能会通过影响调节序列的功能，但是它们如何通过基因促进疾病的确切机制法规仍然未知。在这里，我们旨在在理解3D方面取得重大进步表观基因组通过映射和分析动态变化来促进大脑发育和疾病在人类前额叶皮层发育期间。我们将首先映射转录组，染色质可访问性和从发育中的前额叶皮层中的六种不同细胞类型中的3D染色质环路，并执行综合性分析以询问染色质相互作用如何控制基因表达和发育。第二，我们会的将3D表观基因组数据集与医学遗传学资源相结合，以了解细胞类型，基因组基因座和疾病因果关系的生物途径将GWAS SNP与其靶基因联系起来。第三，到建立染色质环与靶基因表达之间的细胞类型特异性功能联系，我们将测试远端调节区域与IPSC模型和原代细胞中启动子相互作用的生物学后果。我们的项目将揭示有关3D表观基因组在大脑发育中的生物学功能的新见解疾病。