Spatiotemporal epigenomic and chromosomal architectural cell atlas of developing human brains

人类大脑发育的时空表观基因组和染色体结构细胞图谱

• 批准号: 10689124
• 负责人: Chongyuan Luo
• 金额: $ 80.81万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10689124
• 关键词: 10 year old; 3-Dimensional; 5 year old; Adult; Alleles; Architecture; Atlases; Automobile Driving; BRAIN initiative; Biological Assay; Birth; Brain; Brain region; Catalogs; Cell Lineage; Cell Nucleus; Cell model; Cells; Childhood; Chromatin; Chromatin Loop; Classification; Complement; Computing Methodologies; Consensus; DNA; DNA Methylation; DNA methylation profiling; Data; Data Analyses; Data Set; Development; Developmental Gene; Disease; Enhancers; Epigenetic Process; Event; Exhibits; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Generations; Genes; Goals; Human; In Situ; Joints; Life; Link; Location; Maps; Mental disorders; Methods; Modality; Modeling; Molecular; Molecular Conformation; Molecular Profiling; Mus; Neocortex; Nucleic Acid Regulatory Sequences; Play; Population; Predisposition; Pregnancy; Process; Property; RNA; RNA methylation; Regulator Genes; Regulatory Element; Research Personnel; Resources; Role; Sampling; Schizophrenia; Sensory; Series; Specific qualifier value; Symptoms; Time; Tissues; Transitional Cell; Variant; age group; autism spectrum disorder; brain cell; cell type; collaboratory; combinatorial; data management; data resource; digital; epigenomics; experience; gene interaction; gene regulatory network; genetic variant; genomic data; impaired brain development; innovation; methylome; multimodality; nano-string; neocortical; neuropsychiatric disorder; nonhuman primate; novel; postnatal period; predictive modeling; prenatal; programs; response; single cell technology; spatiotemporal; stem cells; tool; transcription factor; transcriptome; transcriptomics

PROJECT SUMMARY The adult human brain is comprised of numerous cell types exhibiting specific transcriptomic and epigenomic signatures associated with their spatial location, connectivity, and function. Although systematic efforts are underway to characterize cell types in the adult human brain, the transitional cell types and cell states in developing human brains are not fully defined. Our project will use epigenomic and three-dimensional (3D) chromosomal architectural information to classify developmental cell types and identify key regulatory dynamics that may underlie cellular lineage commitment and maturation. Single-cell DNA methylation and chromatin accessibility profiles have been successfully used to de novo identify distinct cell types in developing and adult brains. The single-nucleus joint profiling of DNA methylation and chromatin conformation by sn-m3C-seq provides unique information to identify enhancer-gene looping and provides a resource to link genetic variants associated with neuropsychiatric disorders to genes. Cell types identified with epigenomic information will be integrated with spatial transcriptomic signatures using our innovative single-cell joint profiling method of transcriptome and DNA methylation snmCT-seq. We will determine the spatial and temporal dynamics of developing brain cell types using multiplexed RNA in situ and Digital Spatial Profiling (DSP) assays. We will apply state-of-the-art approaches to integrate multiple data modalities to identify progenitor and transitional cell types, lineage-specific regulatory elements, and enhancer-gene 3D interactions. We will construct cell-type- specific predictive models of cellular trajectory and gene regulation during brain development by integrating transcription factor-gene interaction information with time- and pseudotime-series genomics data. The cell type and regulatory elements catalog of human brain development generated by our project will aid the identification of developing brain cell types involved in neuropsychiatric disorders and regulatory regions susceptible to perturbation by disease-associated variants.

项目概要 成人大脑由多种具有特定转录组和表观基因组的细胞类型组成 与其空间位置、连通性和功能相关的特征。尽管系统性的努力 正在进行表征成人大脑中的细胞类型、过渡细胞类型和细胞状态 人类大脑的发育尚未完全定义。我们的项目将使用表观基因组和三维（3D） 染色体结构信息可对发育细胞类型进行分类并识别关键的调控动态 这可能是细胞谱系定型和成熟的基础。单细胞 DNA 甲基化和染色质 可访问性概况已成功用于从头识别发育中和成人中的不同细胞类型 大脑。通过 sn-m3C-seq 对 DNA 甲基化和染色质构象进行单核联合分析 提供独特的信息来识别增强子基因循环，并提供链接遗传变异的资源 与神经精神疾病的基因有关。通过表观基因组信息鉴定的细胞类型将被 使用我们创新的单细胞联合分析方法与空间转录组特征集成 转录组和 DNA 甲基化 snmCT-seq。我们将确定空间和时间动态 使用多重 RNA 原位分析和数字空间分析 (DSP) 分析来开发脑细胞类型。我们将 应用最先进的方法整合多种数据模式来识别祖细胞和过渡细胞 类型、谱系特异性调控元件和增强子基因 3D 相互作用。我们将构建细胞类型- 通过整合大脑发育过程中细胞轨迹和基因调控的特定预测模型 转录因子-基因相互作用信息与时间和伪时间序列基因组学数据。细胞类型 我们的项目生成的人脑发育调控元件目录将有助于识别 发育中的脑细胞类型涉及神经精神疾病和易受影响的调节区域 疾病相关变异的干扰。