A regulome and transcriptome atlas of fetal and adult human neurogenesis

项目概要 顺式调控 DNA 上转录因子结合的时空模式的动态变化 元素在神经发生过程中驱动细胞谱系的发育转变。在人脑中，神经元 是从早期胚胎发育直至产后早期阶段产生的。主要神经发生区 成人的大脑是海马体中的齿状回。虽然成人海马神经发生已 在大多数哺乳动物中得到证实，但尚不清楚这种现象是否存在于人脑中。多个 神经精神疾病，包括抑郁症、精神分裂症和阿尔茨海默病，其根源在于 海马体缺陷。尽管 角色 因此， on及其明显的重要性 在神经发生中，我们对细胞多样性和组织组织的理解非常不完整。 一个 齿状回神经精神疾病， 对齿状回一生进行更完整的细胞普查将增加我们对 胎儿、产后早期和成人神经发生的机制，可能在神经发生中发挥关键作用 人类疾病的病因学。 工具 染色质 回 世界 计算性的 资源 我们提案的总体目标是优化和加速可扩展技术的使用 对基因表达进行公正的、多模式的、基于单核组学的评估 可及性与人类组织切片的空间转录组学分析相结合 跨阶段。在这项研究中，我们聚集了一个跨学科团队 专家解剖学、空间转录组学、神经发育和 生物学创建齿状回细胞普查，该普查将与现有的相结合 来自 BRAIN Initiative 细胞普查网络，并将免费提供给科学界 有齿状的 胎儿、产后早期和成人 在单细胞组学中，人类 社区。 分析 早 胚胎的 海马体 和 这个 利用来自人类齿状回的大量组学数据资源，我们将执行以下三项任务 其目的是：（1）确定胎儿中人类齿状回的细胞多样性和组织结构， 产后和成年阶段； (2) 揭示与相关的共享和独特的基因调控网络 和成人海马神经发生； (3) 研究演化守恒 通过与小鼠和非人类灵长类单细胞进行比较分析来观察神经发生 可通过 BRAIN Initiative 细胞普查网络轻松获取空间转录组数据。 创新研究计划如果成功，将为多模式和空间提供可扩展的技术 齿状细胞类型多样性的组学分析和发育和成体细胞图谱 回 ，这将 作为研究人类海马神经发生、细胞类型选择性脆弱性的蓝图 疾病，以及区分人类与其他物种的大脑进化特征。

PROJECT SUMMARY Dynamic changes in the spatiotemporal patterning of transcription factor binding on cis-regulatory DNA elements drives the developmental transition of cell lineages during neurogenesis. In the human brain, neurons are generated from early embryonic development until early postnatal stages. The main neurogenic region in the adult brain is the dentate gyrus in the hippocampus. While adult hippocampal neurogenesis has been confirmed in the majority of mammals, it is unclear if this phenomenon exists in the human brain. Multiple neuropsychiatric conditions, including depression, schizophrenia and Alzheimer's disease are rooted in hippocampal defects. Despite role Therefore, the obvious importance of on and its in neurogenesis, our understanding of the cell diversity and tissue organization is highly incomplete. a dentate gyrus neuropsychiatric conditions, more complete cell census of the dentate gyrus across lifetime will increase our understanding of the mechanisms underlying fetal, early postnatal and adult neurogenesis, which could have a key role in the etiology of disease in humans. tools chromatin gyrus world computational resources The overarching goal of our proposal is to optimize and accelerate the use of scalable technologies and to perform unbiased, multimodal single-nucleus omics-based assessment of gene expression and accessibility combined with spatial transcriptomics profiling on tissue sections of human across stages. In this study, we bring together an interdisciplinary team of experts anatomy, spatial transcriptomics, neurodevelopment and biology to create a cell census of the dentate gyrus that will be integrated with existing from the BRAIN Initiative Cell Census Network and will be made freely available to the scientific dentate fetal, early postnatal and adult in single cell omics, human community. analyses early embryonic hippocampal and This Utilizing this large resource of omics data from the human dentate gyrus, we will perform the following three that aim to: (1) identify the cell diversity and tissue organization of human dentate gyrus across fetal, postnatal and adult stages; (2) uncover shared and distinct gene regulatory networks associated with and adult human hippocampal neurogenesis; and (3) study the evolution conservation of neurogenesis by performing comparative analysis with mouse and non-human primate single-cell spatial transcriptomic data that are readily accessible through the BRAIN Initiative Cell Census Network. innovative research program will, if successful,provide scalable technologies for multimodal and spatial omics profiling and a developmental and adult cell atlas of cell type diversity in the dentate gyrus , which will serve as a blueprint for studies of human hippocampal neurogenesis, selective vulnerability of cell types in disease, and the features of brain evolution that differentiates humans from other species.