A regulome and transcriptome atlas of fetal and adult human neurogenesis

项目总结 转录因子与顺式调控DNA结合的时空模式的动态变化 在神经发生过程中，元素驱动细胞谱系的发育转变。在人类大脑中，神经元 是从早期胚胎发育到出生后早期阶段产生的。中的主要神经源性区域 成年人的大脑是海马体中的齿状回。而成年海马区的神经发生 在大多数哺乳动物中得到证实，目前尚不清楚这种现象是否存在于人类大脑中。多重 神经精神疾病，包括抑郁症、精神分裂症和阿尔茨海默病，根植于 海马区缺陷症。尽管 角色 因此， On及其应用程序的重要性显而易见 在神经发生中，我们对细胞多样性和组织结构的了解是非常不完整的。 一个 齿状回神经精神疾病， 对齿状回进行更完整的终身细胞普查将增加我们对 胎儿、出生后早期和成人神经发生的机制，这可能在 人类疾病的病因学。 工具 染色质 脑回 世界 计算型 资源 我们提案的总体目标是优化和加快可扩展技术和 对基因表达进行无偏倚的、基于多模式单核组学的评估 可及性结合空间转录图谱在人体组织切片上的应用 跨越不同阶段。在这项研究中，我们汇集了一个跨学科的团队 专家解剖、空间转录学、神经发育和 生物学将创建齿状回细胞普查，这将与现有的 来自大脑倡议细胞普查网络，将免费提供给科学工作者 具牙齿的 胎儿、出生后早期和成人 在单细胞组学中，人类 社区。 分析 早些时候 胚胎 海马区 和 这 利用来自人类齿状回的大量组学数据，我们将进行以下三项工作 其目的是：(1)鉴定人胎儿齿状回的细胞多样性和组织结构， 出生后和成年阶段；(2)发现与以下方面相关的共同和独特的基因调控网络 和成年人的海马神经发生；以及(3)研究 小鼠和非人灵长类单细胞神经发生的比较分析 通过大脑倡议细胞普查网络很容易获得的空间转录数据。 如果成功，创新的研究计划将为多式联运和空间技术提供可扩展的技术 齿状体内细胞类型多样性的组学图谱和发育及成体细胞图谱 脑回 ，这将是 作为研究人类海马神经发生的蓝图，细胞类型的选择性易损性 疾病，以及将人类与其他物种区分开来的大脑进化特征。

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.