A regulome and transcriptome atlas of fetal and adult human neurogenesis

项目摘要 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，这些元素驱动细胞谱系的发育转变。在人脑中，神经元 从早期胚胎发育到出生后早期阶段。脑内主要的神经原性区域 成年人的大脑是海马体中的齿状回。虽然成年海马神经发生一直是 虽然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类大脑中。多 神经精神疾病，包括抑郁症，精神分裂症和阿尔茨海默氏病，其根源在于 海马缺陷尽管 作用 因此，我们认为， 的明显重要性及其 在神经发生中，我们对细胞多样性和组织结构的理解是非常不完整的。 一 齿状回神经精神病症， 更完整的齿状回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，这可能在神经发生中起关键作用。 人类疾病的病因学。 工具 染色质 回 世界 计算 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， 对基因表达进行无偏的、多模式的单核组学评估， 可及性结合人类组织切片的空间转录组学分析 跨阶段。在这项研究中，我们汇集了一个跨学科的团队， 专家解剖学、空间转录组学、神经发育和 生物学创建齿状回的细胞普查，将与现有的 从大脑倡议细胞普查网络，并将免费提供给科学 齿状 胎儿、产后早期和成人 在单细胞组学中，人类 社区 分析 早期 胚胎 海马 和 这 利用人类齿状回的大量组学数据，我们将执行以下三个 目的：（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）揭示与以下疾病相关的共享和独特的基因调控网络： 和成年人海马神经发生;（3）研究海马神经元的进化保守性。 通过对小鼠和非人灵长类动物单细胞进行比较分析， 空间转录组学数据可以通过BRAIN Initiative Cell Census Network轻松访问。 如果成功，创新研究计划将为多模式和空间 齿状突细胞类型多样性的组学分析和发育与成体细胞图谱 回 ，该功能将 作为人类海马神经发生研究的蓝图， 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.