Spatiotemporal epigenomic and chromosomal architectural cell atlas of developing human brains

项目摘要 成年人脑由许多细胞类型组成，表现出特定的转录组和表观基因组 与其空间位置、连通性和功能相关的特征。虽然系统的努力， 正在进行的表征成人大脑中的细胞类型，过渡细胞类型和细胞状态， 人类大脑的发育还没有完全定义。我们的项目将使用表观基因组和三维（3D） 染色体结构信息，用于对发育细胞类型进行分类，并确定关键的调控动力学 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 可及性谱已成功地用于从头鉴定发育和成人中的不同细胞类型 大脑应用sn-m3 C-seq进行DNA甲基化和染色质构象的单核联合分析 提供了独特的信息，以确定增强子基因环，并提供了一个资源，以链接遗传变异 与神经精神疾病相关的基因将使用表观基因组信息鉴定细胞类型。 使用我们创新的单细胞联合分析方法， 转录组和DNA甲基化snmCT-seq.我们将确定的空间和时间动态的 使用多重RNA原位和数字空间轮廓（DSP）分析开发脑细胞类型。我们将 应用最先进的方法来整合多种数据模式，以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- 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。的细胞类型 我们的项目所产生的人脑发育调控元件目录将有助于识别 发展中的脑细胞类型涉及神经精神疾病和调节区域易受 疾病相关变异的干扰。

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.